JP2010248209A - Nitrosated and nitrosylated nonsteroidal antiinflammatory compounds, compositions and methods of use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a nonsteroidal antiinflammatory compound which does not have a side effect which accompanies a compound of prior art, and to provide a novel and improved method for treating inflammatory disease states and disorders, and for treating and/or preventing ophthalmic diseases or disorders. <P>SOLUTION: A nitrogen monoxide group (NO) and/or a nitrogen dioxide group (NO2) are bonded with the nonsteroidal antiinflammatory compound, and the obtained compound has an excellent bioavailability, and an efficacy as an analgesic and antiphlogistic, and has a possibility of forming a gastroenteric damage (ulcer) which is reduced unexpectedly. Moreover, the obtained compound has an unexpected aspect in treating and/or preventing ophthalmic diseases and disorders. The nitrosated and/or nitrosylated nonsteroidal antiinflammatory compounds provide methods for treating, preventing and/or reducing inflammation, pain, and fever; decreasing or reversing the gastrointestinal, renal and other toxicities resulting from the use of nonsteroidal antiinflammatory drugs. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

(Related application)
This application is a continuation-in-part of US patent application Ser. No. 09 / 182,433, filed Oct. 30, 1998.

(Technical field)
The present invention provides at least one of a novel nitrosated and / or nitrosylated non-steroidal anti-inflammatory drug, and a nitrosated and / or nitrosylated non-steroidal anti-inflammatory drug, and optionally nitric oxide, It relates to novel compositions comprising at least one compound that metastasizes or releases, increases endogenous levels of endothelium-derived relaxing factor, stimulates endogenous production of nitric oxide, or is a substrate for nitric oxide synthase. The present invention also provides a method of treating, preventing and / or reducing inflammation, pain and fever; a method of reducing or restoring gastrointestinal, renal or other toxicities through the use of non-steroidal anti-inflammatory compounds; Or methods of treating; methods of treating inflammatory disease states and disorders; and methods of treating and / or preventing ophthalmic diseases or disorders.

(Background of the Invention)
Chemistry and pharmacology of nitroxybutyl ester ((CH ₂ ) ₄ -ONO ₂ ) derivatives of a number of arylpropionic acid non-steroidal anti-inflammatory compounds including ketoprofen, flurbiprofen, suprofen, indobufen and etodolac It is described in WO94 / 12463 (Patent Document 1). Studies on flurbuprofen and nitroxybutyl esters of ketoprofen are also reported in Wallace et al., Gastroenterology, 107: 173-179 (1994) (Non-patent Document 1). See also the following references: Cuzzolin et al., Pharmacol. Res. 29 (1): 89-97 (1994) (Non-Patent Document 2); Reuter et al., Life Sci. (USA), 55/1 (PL1-PL8) (1994) (Non-Patent Document 3); Reuter et al., Gastroenterology, 106 (4): Suppl. A759 (1994) (Non-Patent Document 4); Wallace et al., Eur. J. et al. Pharmacol. 257 (3): 249-255 (1994) (Non-Patent Document 5); Wallace et al., Gastroenterology, 106 (4): Suppl. A208 (1994) (Non-Patent Document 6); and Comforti et al., Agents-Actions, 40 (3-4): 176-180 (1993) (Non-Patent Document 7). These publications consider and rely on the use of uniformly and indirectly attached nitrogen dioxide substitution.

  US Pat. No. 5,703,073 discloses a non-steroidal anti-inflammatory compound containing a nitric acid group indirectly linked to a non-steroidal anti-inflammatory compound, and usually a non-steroidal anti-inflammatory compound. The protection of the compound against gastrointestinal, renal and other toxicities induced by is described. The compounds described in US Pat. No. 5,703,073 all contain heteroatoms that are flanked by carbonyl groups in the form of esters, amides or thioesters in the bond backbone.

  The use of non-steroidal anti-inflammatory compounds for the treatment and / or prevention of ophthalmic diseases or disorders such as glaucoma, ophthalmitis and elevated intraocular pressure has been described. For example, US Pat. No. 5,474,985 uses non-steroidal anti-inflammatory compounds for the treatment or prevention of non-inflammatory induction, elevated intraocular pressure associated with the administration of corticosteroids. Is described. U.S. Pat. Nos. 5,674,888 and 5,599,535 describe environmental stresses such as aging, exposure to toxic substances, oxidative or phagocytic injury, Or use non-steroidal anti-inflammatory compounds to treat trabecular meshwork loss caused by glucocortico exposure. US Pat. No. 5,814,655 describes a topical ophthalmic composition containing a non-steroidal anti-inflammatory compound. Wiederholt et al., Invest. Optalmol. Vis. sci. , 2515-2520 (1994), describes the use of nitric oxide donors for relaxation of trabecular meshwork and ciliary muscle. Behar-Cohe et al., Invest. Optalmol. Vis. sci. (Non-Patent Document 9) describes the use of a nitric oxide donor to reduce intraocular pressure.

  There is a need in the art for non-steroidal anti-inflammatory compounds that do not have the side effects associated with prior art compounds. There is also a need for new and improved treatments for inflammatory disease states and disorders, as well as ophthalmic diseases and disorders. The present invention is directed to these and other important objectives.

PCT Application No. WO94 / 12463 US Pat. No. 5,703,073 US Pat. No. 5,474,985 US Pat. No. 5,674,888 US Pat. No. 5,599,535 US Pat. No. 5,814,655

Wallace et al., Gastroenterology, 107: 173-179 (1994). Cuzzolin et al., Pharmacol. Res. 29 (1): 89-97 (1994). Reuter et al., Life Sci. (USA), 55/1 (PL1-PL8) (1994) Reuter et al., Gastroenterology, 106 (4): Suppl. A759 (1994) Wallace et al., Eur. J. et al. Pharmacol. 257 (3): 249-255 (1994) Wallace et al., Gastroenterology, 106 (4): Suppl. A208 (1994) Comforti et al., Agents-Actions, 40 (3-4): 176-180 (1993). Wiederholt et al., Invest. Optalmol. Vis. sci. , 2515-2520 (1994) Behar-Cohe et al., Invest. Optalmol. Vis. sci.

(Summary of the Invention)
The present invention is capable of binding a nitric oxide group (NO) and / or a nitrogen dioxide group (NO ₂ ) (ie, nitrosylated and / or nitrosated groups, respectively) to a nonsteroidal anti-inflammatory compound, and the resulting compound It is based on the discovery that it has excellent bioavailability, is effective as an analgesic and anti-inflammatory agent, and has the potential to produce unexpectedly reduced gastrointestinal damage (ulcers). The new compounds also have unexpected properties for the treatment and / or prevention of ophthalmic diseases and disorders.

  The present invention also relates to NSAID-induced gastrointestinal tracts by administering at least one nitrosated and / or nitrosylated non-steroidal anti-inflammatory compound (NSAID) and at least one nitric oxide donor. Based on the discovery that it is possible to prevent, reduce or ameliorate kidney and other toxicities. NSAIDs are prostaglandins and cyclooxygenases that are enzymes involved in the biosynthesis of certain autocidal inhibitors including inhibitors of various cyclooxygenases (including but not limited to cyclooxygenase-1 and -2). On the other hand, it is an anti-inflammatory, analgesic and antipyretic compound that acts as an inhibitor of both cyclooxygenase and lipooxygenase. Nitric oxide donors are compounds that contain a nitric oxide moiety and release nitric oxide or chemically transfer nitric oxide to other molecules. Nitric oxide donors include, for example, S-nitrosothiols, nitrites, N-oxo-N-nitrosamines, and various nitric oxide synthase isozyme substrates.

  One aspect of the present invention provides novel nitrosated and / or nitrosylated non-steroidal anti-inflammatory compounds. Non-steroidal anti-inflammatory compounds can be nitrosated and / or nitrosylated via one or more sites such as oxygen (hydroxy condensation), sulfur (sulfhydryl condensation), carbon and / or nitrogen. The non-steroidal anti-inflammatory compound can be, for example, an arylpropionic acid, an arylacetic acid or an enol-type anilide. The present invention also provides compositions containing these compounds in a pharmaceutically acceptable carrier.

Another aspect of the present invention is to provide a therapeutically effective amount of at least one nitrosated and / or nitrosylated non-steroidal anti-inflammatory compound and a nitric oxide charged species, ie nitrosonium (NO ⁺ ) or nitroxyl. Donate, transfer or release as (NO ⁻ ) or as a neutral species, ie nitric oxide (NO.), And / or stimulate endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo And / or a composition comprising at least one compound that is a substrate for nitric oxide synthase. The present invention also provides a composition comprising the composition in a pharmaceutically acceptable carrier.

Yet another aspect of the present invention is to provide at least one nitrosated and / or nitrosylated non-steroidal anti-inflammatory compound and optionally a nitric oxide as a charged species, ie nitrosonium (NO ⁺ ) or nitroxyl (NO ^- ) Or as a neutral species, ie nitric oxide (NO.), Donate, transfer or release, and / or stimulate endogenous production of nitric oxide or EDRF in vivo and / or of nitric oxide synthase A kit comprising at least one compound as a substrate is provided. The nitrosated and / or nitrosylated NSAID and the nitric oxide donor can be separate components in the kit and can be in the form of one composition.

The invention also provides a method of treating and / or preventing inflammation, pain and fever; a method of reducing and / or ameliorating gastrointestinal, renal and other toxicities resulting from the use of non-steroidal anti-inflammatory compounds; At least one nitrosated and / or nitrosylated non-steroidal anti-inflammatory compound and optionally nitric oxide as a charged species, ie nitrosonium (NO ⁺ ) or nitroxyl (NO ⁻ ), or Donate, transfer or release as a neutral species or nitric oxide (NO.) And / or stimulate endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and / or nitric oxide synthase Administration of at least one compound serving as a substrate for the treatment of gastrointestinal disorders in patients in need of treatment or prevention And / or methods of prevention. Nitrosated and / or nitrosylated NSAIDs and nitric oxide donors can be administered separately or as components of the same composition.

  The invention also administers a therapeutically effective amount of at least one nitrosated and / or nitrosylated non-steroidal anti-inflammatory compound and optionally at least one nitrogen donor to a patient in need of treatment. Thereby providing a method of treating inflammatory disease states and disorders. The nitrosated and / or nitrosylated NSAID and nitric oxide donor can be administered separately or as components of the same composition. Such inflammatory disease states and disorders include, for example, reperfusion injury to ischemic organs (eg, reperfusion injury to ischemic myocardium), myocardial infarction, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis , Hypertension, psoriasis, organ transplant rejection, organ preservation, female or male sexual dysfunction, radiation-induced damage, asthma, atherosclerosis, thrombosis, platelet aggregation, restenosis, metastasis, influenza, incontinence, seizures, burns, Trauma, acute pancreatitis, pyelonephritis, hepatitis, autoimmune disease, immunodeficiency, senile dementia, insulin-dependent diabetes, disseminated intravascular coagulation, fat embolism, Alzheimer's disease, adult or infant respiratory disease, carcinogenesis or bleeding in newborns including.

The present invention also requires treatment and / or prevention of a therapeutically effective amount of at least one nitrosated and / or nitrosylated non-steroidal anti-inflammatory compound and optionally at least one nitrogen donor. The present invention provides a method for treating and / or preventing ophthalmic diseases and disorders by administering to a patient. Ocular diseases and disorders include glaucoma, ophthalmitis and elevated intraocular pressure. Nitrosated and / or nitrosylated NSAIDs and nitric oxide donors can be administered separately or as components of the same composition.
These and other aspects of the invention are described in detail below.

(Detailed description of the invention)
Throughout this specification, the following terms have the meanings defined below, unless otherwise specified.
The term “Gastrointestinal disorder” refers to a disease or injury of the patient's upper gastrointestinal tract, eg, peptic ulcer, stress ulcer, hyperacidity, dyspepsia, gastric insufficiency, Zollinger-Ellison syndrome, stomach Hyperesophageal conditions associated with esophageal reflux disease, short bowel (anastomosis) syndrome, or systemic mastocytosis or basophilic leukemia and hyperhistamine, and neurosurgery, head injury, severe physical trauma or burns, for example Including hemorrhagic peptic ulcers derived from

  The term “Upper gastrointestinal tract” refers to the esophagus, stomach, duodenum and jejunum.

  The term “Ulcers” refers to damage to the upper gastrointestinal lining characterized by tissue loss. This ulcer includes gastric ulcer, duodenal ulcer and gastritis.

  The term “NSAID” refers to a non-steroidal anti-inflammatory compound or a non-steroidal anti-inflammatory drug. NSAIDs are prostaglandins and cyclooxygenases that are enzymes involved in the biosynthesis of certain autocidal inhibitors, including inhibitors of the isozymes of various cyclooxygenases, including but not limited to cyclooxygenase-1 and -2. And acts as an inhibitor of both cyclooxygenase and lipooxygenase.

  The term “patient” refers to an animal, preferably a mammal, more preferably a human.

  The term “transdermal” refers to the delivery of a drug through the skin and into the bloodstream.

  The term “transmucosal” refers to the delivery of a drug through mucosal tissue and into the bloodstream.

  The term “penetration enhancement” or “permeation enhancement” refers to an increase in the permeability of the skin or mucosal tissue to a selected pharmacologically active substance, whereby the drug is cut into the skin. Or the rate of permeation through mucosal tissue is increased.

  The term “carrier” or “vehicle” refers to a support material used to properly administer the drug, such as various liquids, gels, solvents, liquid diluents, solubilizers, Substances known to those skilled in the art, such as analogs, that are not toxic and do not interact adversely with any ingredients in the composition.

The term “nitric oxide adduct” or “NO adduct” is used to indicate that, under physiological conditions, the biological action of a nitric oxide species is exerted at the intended point of action. Compounds and functionalities capable of donating, releasing and / or directly or indirectly transferring any of the three redox forms of nitrogen (NO ⁺ , NO ⁻ , NO.) Represents a group.

The terms “nitric oxide releasing” or “nitric oxide donating” are used so that the biological action of the nitric oxide species is exerted at the point of action of interest. It represents a method of donating, releasing and / or transferring directly or indirectly one of the three redox forms of nitric oxide (NO ⁺ , NO ⁻ , NO.).

  The term “nitric oxide donor” or “NO donor” refers to compounds that donate, release and / or directly or indirectly transfer nitric oxide species, and / or nitric oxide in vivo. Or a compound that stimulates the endogenous production of endothelium-derived relaxing factor (EDRF) and / or a compound that increases endogenous levels of nitric oxide or EDRF in vivo. The term “NO donor” further includes compounds that are substrates for nitric oxide synthase.

  The term “alkyl” represents a lower alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group, or a heterocyclic ring, as defined herein.

  The term “lower alkyl” refers to a branched or straight chain acyclic alkyl group of 1 to about 10 carbon atoms (preferably 1 to about 8, more preferably 1 to about 6 carbon atoms). It contains atoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl, and the like.

  The term “haloalkyl” is a lower alkyl group, alkenyl group, alkynyl group, bridged cycloalkyl group, cycloalkyl group, or heterocyclic ring (as defined herein), These are those with one or more halogens as defined herein. Illustrative of haloalkyl groups are trifluoromethyl, chloromethyl, 2-bromobutyl, 1-bromo-2-chloropentyl, and the like.

The term “alkenyl” refers to a branched or straight chain C ₂ -C ₁₀ hydrocarbon (preferably a C ₂ -C ₈ hydrocarbon, more preferably a C ₂ -C ₆ hydrocarbon), one or more The thing containing the carbon-carbon double bond of this is represented. Examples of alkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexane-1-yl, heptene-1 -Yl, octen-1-yl, and the like.

The term “alkynyl” refers to an unsaturated acyclic C ₂ -C ₁₀ hydrocarbon (preferably a C ₂ -C ₈ hydrocarbon, more preferably a C ₂ -C ₆ hydrocarbon), wherein one or more carbon- The thing containing a carbon triple bond is represented. Examples of alkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl 2-yl, hexyl-3-yl, 3,3-dimethylbutyn-1-yl, and the like.

  The term “bridged cycloalkyl” refers to two or more cycloalkyl groups, heterocyclic groups, or combinations thereof fused through adjacent or non-adjacent atoms. . A bridged cycloalkyl group may be unsubstituted or substituted, but when substituted, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alkylcarboxylic acids Substituted with 1, 2 or 3 substituents independently selected from aryl, amidyl, ester, alkyl carboxylic acid ester, carboxamide, alkyl carboxamide, oxo and nitro. Examples of bridged cycloalkyl groups include adamantyl, decahydronaphthyl, quinuclidyl, 2,6-dioxabicyclo [3.3.0] octane, 7-oxabicyclo [2.2.1] heptyl, 8 -Azabicyclo [3,2,1] oct-2-enyl, and the like.

  The term “cycloalkyl” refers to a saturated or unsaturated alicyclic group containing from about 3 to about 8 carbon atoms. Cycloalkyl groups can be unsubstituted or substituted, but when substituted, alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, aryl, amidyl Substituted with 1, 2 or 3 substituents independently selected from ester, hydroxy, halo, carboxyl, alkyl carboxylic acid, alkyl carboxylic acid ester, carboxamide, alkyl carboxamide, oxo and nitro. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like.

  The term “heterocyclic ring or group” is a cyclic hydrocarbon group having about 2 to 10 carbon atoms (preferably about 4 to about 6 carbon atoms), saturated or unsaturated, of which In which from 1 to about 4 carbon atoms are replaced by one or more nitrogen, oxygen and / or sulfur atoms. The heterocyclic ring or group may be fused with an aromatic hydrocarbon group. The heterocyclic group may be unsubstituted or substituted, but when substituted, alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, hydroxy, 1, 2 or 3 substitutions independently selected from oxo, halo, carboxyl, carboxylic acid ester, alkyl carboxylic acid, alkyl carboxylic acid ester, aryl, amidyl, ester, carboxamide, alkyl carboxamide, aryl carboxamide, sulfonyl and nitro Substituted with a group. Illustrative heterocyclic groups include pyrrolyl, 3-pyrrolinyl, 4,5,6-trihydro-2H-pyranyl, pyridinyl, 1,4-dihydropyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, Imidazolyl, indolyl, thiophenyl, furanyl, tetrahydrofuranyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, oxazolinedinyl, 1,3-dioxolanyl, 2-imidazolinyl, imidazolindinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpho Alkenyl is 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo (b) thiophenyl, benzimidazolyl, quinolinyl, and the like.

  The term “heterocyclic compound” refers to monocyclic and polycyclic compounds containing at least one aryl or heterocyclic ring.

  The term “aryl” refers to a monocyclic, bicyclic, carbocyclic, or heterocyclic ring system having one or two aromatic rings. Illustrative aryl groups include phenyl, pyridyl, naphthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl, and the like. Aryl groups (including bicyclic aryl groups) may be unsubstituted or substituted, but when substituted, alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, Substituted with 1, 2 or 3 substituents independently selected from alkylarylamino, hydroxy, carboxy, alkyl carboxylic acid, alkyl carboxylic acid ester, aryl, amidyl, ester, carboxamide, alkyl carboxamide, and nitro. Illustrative examples of substituted aryl groups include tetrafluorophenyl, pentafluorophenyl, sulfonamido, alkylsulfonyl, arylsulfonyl, and the like.

  The term “alkylaryl” refers to an alkyl group, as defined herein, appended with an aryl group, as defined herein. Illustrative alkylaryl groups are benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl, and the like.

  The term “arylalkyl” refers to an aryl radical, as defined herein, attached to an alkyl radical, as defined herein.

  The term “cycloalkylalkyl” refers to a cycloalkyl radical as defined herein attached to an alkyl radical as defined herein.

  The term “heterocyclic alkyl” refers to a heterocyclic ring radical as defined herein attached to an alkyl radical as defined herein.

  The term “aryl heterocyclic ring” means that an aryl ring as defined herein is attached to a heterocyclic ring as defined herein via two adjacent carbon atoms of the aryl ring. It represents a bicyclic ring or a tricyclic ring. Examples of aryl heterocyclic rings include dihydroindole, 1,2,3,4-tetra-hydroquinoline, and the like.

The term “alkoxy” refers to R ₅₀ O—, wherein R ₅₀ is an alkyl group as defined herein. Illustrative examples of alkoxy groups include methoxy, ethoxy, t-butoxy, cyclopentyloxy, and the like.

  The term “arylalkoxy or alkoxyaryl” refers to an alkoxy group as defined herein appended with an aryl group as defined herein. Examples of arylalkoxy groups are benzyloxy, phenylethoxy, chlorophenylethoxy, and the like.

  The term “alkoxyalkyl” refers to an alkoxy group, as defined herein, appended to an alkyl group, as defined herein. Illustrative examples of alkoxyalkyl groups include methoxymethyl, methoxyethyl, isopropoxymethyl, and the like.

  The term “alkoxyhaloalkyl” refers to an alkoxy group, as defined herein, appended to a haloalkyl group, as defined herein. An example of an alkoxyhaloalkyl group is 4-methoxy-2-chlorobutyl.

The term “cycloalkoxy” represents R ₅₄ O—, wherein R ₅₄ is a cycloalkyl group or a bridged cycloalkyl group as defined herein. Examples of the cycloalkoxy group include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

  The term “haloalkyl” refers to a haloalkyl group, as defined herein, appended with an alkoxy group, as defined herein. Illustrative haloalkyl groups are 1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.

  The term “hydroxy” refers to —OH.

  The term “oxo” represents ═O.

The term “oxy” represents —O ^— R ₇₇ ⁺ , where R ₇₇ is an organic or inorganic cation.

  The term “hydroxyalkyl” refers to a hydroxyl group as defined herein attached to an alkyl group as defined herein.

The term “amino” refers to —NH ₂ .

The term “nitrate ester” represents —O—NO ₂ .

  The term “nitrite” represents —O—NO.

The term “thionitrate” refers to —S—NO ₂ .

  The terms “thionitrite” and “nitrosothiol” represent —S—NO.

The term “nitro” refers to the group —NO _2, and the term “nitrosation” refers to a compound substituted thereby.

  The term “nitroso” refers to the group —NO, and the term “nitrosylation” refers to a compound substituted thereby.

  The terms “nitrile” and “cyano” represent —CN.

  The term “halogen” or “halo” represents iodine (I), bromine (Br), chlorine (Cl) and / or fluorine (F).

The term “alkylamino” refers to R ₅₀ NH—, wherein R ₅₀ is an alkyl group as defined herein. Examples of alkylamino groups are methylamino, ethylamino, butylamino, cyclohexylamino, and the like.

The term “arylamino” refers to R ₅₅ NH—, wherein R ₅₅ is an aryl group as defined herein.

The term “dialkylamino” refers to R ₅₂ R ₅₃ N—, wherein R ₅₂ and R ₅₃ are each independently an alkyl group, as defined herein. Examples of dialkylamino groups are dimethylamino, diethylamino, methylpropargylamino, and the like.

The term “diarylamino” refers to R ₅₅ R ₆₀ N—, wherein R ₅₅ and R ₆₀ are each independently an aryl group, as defined herein.

The term “alkylarylamino” refers to R ₅₂ R ₅₅ N—, wherein R ₅₂ is an alkyl group, as defined herein, and R ₅₅ is an aryl group, as defined herein.

  The term “aminoalkyl” is defined herein as an amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino or heterocyclic ring as defined herein. Represents an alkyl group attached.

  The term “aminoaryl” is defined herein as an amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino or heterocyclic ring as defined herein. Represents an attached aryl group.

  The term “sulfinyl” represents —S (O) —.

The term “sulfonyl” refers to —S (O) ₂ —OR ₅₈ , wherein R ₅₈ is an alkyl group, an aryl group, an alkylaryl group, or an aryl heterocyclic ring as defined herein.

The term “sulfonic acid” represents —S (O) ₂ OR ₇₆ , where R ₇₆ is hydrogen, an organic cation or an inorganic cation.

  The term “alkylsulfonic acid” refers to an alkyl group as defined herein appended with a sulfonic acid group as defined herein.

  The term “aryl sulfonic acid” refers to an aryl group as defined herein appended with a sulfonic acid group as defined herein.

The term “sulfonate ester” refers to —S (O) ₂ OR ₅₈ , wherein R ₅₈ is an alkyl group, aryl group, alkylaryl group, or aryl heterocyclic ring as defined herein. is there.

The term “sulfonamide” refers to —S (O) ₂ —N (R ₅₁ ) (R ₅₇ ), wherein R ₅₁ and R ₅₇ are each independently a hydrogen atom as defined herein, An alkyl group, an aryl group, an alkylaryl group, or an aryl heterocyclic ring, and when R ₅₁ and R ₅₇ are bonded to each other, a heterocyclic ring, a cycloalkyl group, as defined herein, Or, it is a cycloalkyl group having a bridge bond.

  The term “alkylsulfonamido” refers to an alkyl group, as defined herein, appended with a sulfonamido group, as defined herein.

  The term “arylsulfonamido” refers to an aryl group, as defined herein, appended with a sulfonamido group, as defined herein.

The term “alkylthio” represents R ₅₀ S—, wherein R ₅₀ is an alkyl group, as defined herein.

The term “arylthio” refers to R ₅₅ S—, wherein R ₅₅ is an aryl group as defined herein.

The term “alkylsulfinyl” refers to R ₅₀ —S (O) —, wherein R ₅₀ is an alkyl group, as defined herein.

The term “alkylsulfonyl” refers to R ₅₀ —S (O) ₂ —, wherein R ₅₀ is an alkyl group, as defined herein.

The term “arylsulfinyl” refers to R ₅₅ —S (O) —, wherein R ₅₅ is an aryl group as defined herein.

The term “arylsulfonyl” refers to R ₅₅ —S (O) ₂ —, wherein R ₅₅ is an aryl group as defined herein.

The term “amidyl” represents R ₅₁ C (O) N (R ₅₇ ) —, wherein R ₅₁ and R ₅₇ are each independently a hydrogen atom, an alkyl group, an aryl group, as defined herein. , An alkylaryl group, or an aryl heterocyclic ring.

The term “ester” represents R ₅₁ C (O) O—, wherein R ₅₁ is a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an aryl heterocyclic ring as defined herein. It is.

The term “carbamoyl” refers to —O—C (O) N (R ₅₁ ) (R ₅₇ ), wherein R ₅₁ and R ₅₇ are each independently a hydrogen atom, alkyl as defined herein. A group, an aryl group, an alkylaryl group, or an aryl heterocyclic ring, and when R ₅₁ and R ₅₇ are bonded to each other, a heterocyclic ring, a cycloalkyl group, or It is a cycloalkyl group having a bridge bond.

The term “carboxyl” represents —C (O) OR ₇₆ where R ₇₆ is hydrogen, an organic cation or an inorganic cation.

  The term “carbonyl” represents —C (O) —.

  The term “methane thial” represents —C (S) —.

  The term “Chiar” represents ═S.

The term “carboxylic acid ester” refers to —C (O) OR ₅₈ , where R ₅₈ is an alkyl group, aryl group, alkylaryl group, or aryl heterocyclic ring as defined herein. .

  The terms “alkylcarboxylic acid” and “alkylcarboxyl” refer to a carboxyl group as defined herein appended to an alkyl group as defined herein.

  The term “alkyl carboxylic acid ester” refers to a carboxylic acid ester group as defined herein appended with an alkyl group as defined herein.

  The term “arylcarboxylic acid” refers to a carboxyl group as defined herein appended with an aryl group as defined herein.

  The term “aryl carboxylic ester” refers to a carboxylic ester group as defined herein appended with an aryl group as defined herein.

The term “carboxamide” represents —C (O) N (R ₅₁ ) (R ₅₇ ), wherein R ₅₁ and R ₅₇ are each independently a hydrogen atom, an alkyl group, An aryl group, an alkylaryl group, or an aryl heterocyclic ring, and when R ₅₁ and R ₅₇ are bonded to each other, a heterocyclic ring, a cycloalkyl group, or a bridge as defined herein; A cycloalkyl group having a bond.

  The term “alkylcarboxamide” refers to a carboxamide group as defined herein appended with an alkyl group as defined herein.

  The term “arylcarboxamide” refers to a carboxamide group as defined herein appended with an aryl group as defined herein.

The term “urea” refers to —N (R ₅₈ ) —C (O) N (R ₅₁ ) (R ₅₇ ), wherein R ₅₁ , R ₅₇ and R ₅₈ are each independently A defined hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an aryl heterocyclic ring, and when R ₅₁ and R ₅₇ are bonded to each other, the heterocyclic group defined herein A ring, a cycloalkyl group, or a cycloalkyl group having a bridge bond.

The term “phosphoryl” refers to —P (R ₇₀ ) (R ₇₁ ) (R ₇₂ ), wherein R ₇₀ is a lone pair, thiar or oxo, and R ₇₁ and R ₇₂ are each independently A covalent bond, hydrogen, lower alkyl, alkoxy, alkylamino, hydroxy, oxy or aryl as defined herein.

The term “silyl” refers to —Si (R ₇₃ ) (R ₇₄ ) (R ₇₅ ), wherein R ₇₃ , R ₇₄ and R ₇₅ are each independently a covalent bond as defined herein, Lower alkyl, alkoxy, aryl or arylalkoxy.

  The NSAID that is nitrosated and / or nitrosylated according to the present invention and / or contained in the composition of the present invention may be any known in the art, including those exemplified below. Good.

  Despite the introduction of a number of new drugs, aspirin (acetylsalicylic acid) is still the most widely prescribed anti-inflammatory, analgesic and antipyretic compound, and a standard to compare and evaluate other NSAIDs. Is done. Since salicylic acid itself is highly irritating, it can be used only as an external preparation. However, derivatives, particularly salicylic acid esters and salts, have been manufactured as providing forms of orally ingestible salicylic acid that have the desired anti-inflammatory and other properties. In addition to aspirin which is an acetic acid ester of salicylic acid, there are difluorophenyl derivatives (diflunisal) and salicylsalicylic acid (salsalate). Salts of salicylic acid are also available, mainly salicylic acid sodium salt. Sodium salicylate and aspirin are the two most commonly used formulations for systemic treatment. Other salicylic acid derivatives include salicylamide, sodium thiosalicylate, choline salicylate and magnesium salicylate. A combination of choline and magnesium salicylate is also available. Further, those used in the present invention include 5-aminosalicylic acid (mesalamine), salicylazosulfapyridine (sulfasalazine) and methyl salicylate.

  Another group of NSAIDs are pyrazolone derivatives, such as phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, dipyrone, and apazone (azapropazone).

  Another group of NSAIDs are para-aminophenol derivatives, so-called “coal tar” analgesics, such as phenacetin and its active metabolite acetaminophen.

  Another group of compounds used in the present invention includes methylated indole derivatives indomethacin and its structurally related compound sulindac.

  Another group of compounds used in the present invention is a derivative of N-phenylanthranilic acid represented as phenate. The best known of these compounds are mefenamic, meclofenamic, flufenamic, tolfenamic and etofenamic acid. These are used as acids or as pharmaceutically acceptable salts.

  Another NSAID used is tolmetin, which, like the other NSAIDs discussed here, causes gastric erosion and prolonged bleeding time.

  Another group of NSAIDs is propionic acid derivatives. The main members of this group include, for example, ibuprofen, naproxen, flurbiprofen, fenoprofen and ketoprofen. Other compounds in this group that are used or discussed in other countries besides the United States include, for example, fenbufen, pyrprofen, oxaprozin, indoprofen and thiaprofenic acid.

Others used in the present invention include piroxicam and ampiroxicam, oxicam derivatives, which are classified as anti-inflammatory enol acids. As other related compounds, tenoxicam and tenidap can be used.
Another particularly preferred compound in the present invention is diclofenac, one of a series of phenylacetic acid derivatives developed as anti-inflammatory compounds. Other NSAIDs suitable in the present invention include etodolac and nabmenton.

  The above NSAIDs are described in, for example, Goodman and Gilman, The Pharmaceutical Basis of Therapeutics (Ninth Edition), McGraw-Hill, 1995, Pgs. 617-657; the Merck Index CD-ROM version, 12th edition, Version 12: 1, 1996, and the like.

  In one embodiment of the invention, a nitrosated and / or nitrosylated NSAID of formula (I) is shown:

Where R _g is a hydrogen atom or a lower alkyl group;
R _h is:

n is an integer of 0 or 1;
X is:
_{(I) -T-B l -W} -B t -T-NO s;
_{(Ii) -T-B l -L} y -B x -T-NO s;
_{(Iii) -T-B l -W} -B t -W x -B k -T-NO s;
_{(Iv) -T-B l -} (C (R b) (R c)) p -E x -T-NO s;
_{(V) -T-B l -G} -B t -W z -B k -G x -B r -T-NO s;
_{(Viii) -T-B l -J} -E x -T-NO s; or _{(ix) -T-B l -C} (R e) = N-E z -T-NO s;
here,
s is an integer of 1 or 2;
T is each independently a covalent bond, carbonyl, oxygen, -S- (O) _o -or -N (R _a ) R _i- ;
o is an integer from 0 to 2;
R _a is a lone pair, hydrogen or an alkyl group;
_Ri is hydrogen, alkyl, aryl, alkylcarboxylic acid, arylcarboxylic acid, alkylcarboxylic acid ester, arylcarboxylic acid ester, alkylcarboxamide, arylcarboxamide, alkylaryl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, sulfonamide , Carboxamide, carboxylic acid ester, aminoalkyl, aminoaryl, —CH ₂ —C (TQ) (R _e ) (R _f ), or — (N ₂ O ₂ —) ⁻ · M ⁺ (where M ⁺ is an organic or inorganic cation);
L is independently —C (O) —, —C (S) —, —T—, a heterocyclic ring, an aryl group, an alkenyl group, an alkynyl group, an aryl heterocyclic ring, or — (CH _2). CH ₂ O) _q ;
q is an integer from 1 to 5;
B is independently an alkyl group, an aryl group, or — (C (R _e ) (R _f )) _p —, a heterocyclic ring, an aryl heterocyclic ring, or — (CH ₂ CH ₂ O) _{q each time.} Is;
p is an integer from 1 to 10;
R _e and R _f are each independently hydrogen, alkyl, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, aryl heterocyclic ring, alkylaryl, cycloalkylalkyl, heterocyclic alkyl, alkoxy, haloalkoxy , Amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, haloalkoxy, sulfonic acid, alkylsulfonic acid, arylsulfonic acid, arylalkoxy, alkylthio, arylthio, cyano, aminoalkyl, aminoaryl , Alkoxy, aryl, arylalkyl, alkylaryl, carboxamide, alkylcarboxamide, arylcarboxamide, amino , Carboxyl, carbamoyl, alkyl carboxylic acid, aryl carboxylic acid, ester, carboxylic acid ester, alkyl carboxylic acid ester, aryl carboxylic acid ester, haloalkoxy, sulfonamide, alkyl sulfonamide, aryl sulfonamide, urea, nitro, -T -NO _s , or [C (R _e ) (R _f )] _k -T-NO _s , or R _e and R _f are bonded together to form a heterocyclic ring, a cycloalkyl group or a bridge A cycloalkyl group having a bond;
R _b and R _c are each independently haloalkyl, alkenyl group, alkynyl group, cycloalkyl group having a bridge bond, heterocyclic ring, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, aryl heterocyclic ring , Alkylaryl, cycloalkylalkyl, heterocyclic alkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, haloalkoxy, sulfonic acid, alkylsulfonic acid, aryl Sulfonic acid, arylalkoxy, alkylthio, arylthio, cyano, aminoalkyl, aminoaryl, alkoxy, arylalkyl, alkylaryl, cation Boxamide, alkylcarboxamide, arylcarboxamide, amidyl, carboxyl, carbamoyl, alkylcarboxylic acid, arylcarboxylic acid, ester, carboxylic acid ester, alkylcarboxylic acid ester, arylcarboxylic acid ester, haloalkoxy, sulfonamide, alkylsulfonamide, arylsulfone Amide, urea, nitro, -T-NO _s , or (C (R _e ) (R _f )) _k -T-NO _s , or R _b and R _c are bonded together to form carbonyl, methanethiol A heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group;
G is a covalent bond, -TC (O)-, -C (O) -T- or T;
J is carbonyl, phosphoryl or silyl;
k, l, t and z are each independently an integer of 1 to 3;
y is an integer from 1 to 3;
x and r are each independently an integer from 0 to 3;
E is independently —C (O) —, —C (S) —, —T—, — (C (R _e ) (R _f )) _p —, an alkyl group, an aryl group, a heterocyclic ring. , aryl heterocyclic ring, or _- be _{(CH 2 CH 2 O) q} ;
W is _{oxygen, -S (O) o -,} - N (R a) R l -, carbonyl, or Metanchiaru;
However, _{R i} is _{-CH 2 -C (T-NO s} ) (R e) (R f) or ^{_{- (N 2 O 2) -}} · M + or where _{R b, R c, R e} or When R _f is -T-NO _s or (C (R _e ) (R _f )) _k -T-NO _s , the subgroup represented by "-T-NO _s " in X is hydrogen, It may be an alkyl, alkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, heterocyclic ring or aryl group.

When multiple variables are listed and "covalent bond" is selected in the molecular sequence or 0 is selected as an integer, the purpose is to bind radicals to each other. It is trying to represent a single covalent bond. For example, B ₀ represents a covalent bond, while B ₂ is (BB) and [C (R _e ) (R _f )] ₂ is —C (R _e ) (R _f ) —C (R _e ) (R _f ) −.

  As another embodiment of the present invention, a nitrosated and / or nitrosylated NSAID of formula (II) is shown:

Where R _k is:

  X is defined in this specification.

  Another embodiment of the present invention shows a nitrosated and / or nitrosylated NSAID of formula (III):

Where X is as defined herein;
R _i is R _i independently each case, wherein R _i is as defined herein;
Z is an aryl group; and A ₁ , A _2, and A ₃ contain other subunits of 5- or 6-membered monocyclic aromatic rings, and each A ₁ , A _2, and A ₃ is independently Is:
(1) C—R _o , where R _o is each independently hydrogen, alkyl, alkoxyalkyl, halogen or nitro group;
(2) N—R _p , where R _p is independently a covalent bond, hydrogen, alkyl, arylalkyl, aryl or heteroaryl group bonded to adjacent ring atoms in order to confer aromaticity to the ring. is there;
(3) sulfur atom;
(4) oxygen atom; or (5) B _a = B _b , wherein B _a and B _b are each independently a nitrogen atom or C—R _o , where R _o is as defined herein. Is.

  As another embodiment of the present invention, a nitrosated and / or nitrosylated NSAID of formula (IV) is shown:

here,
R _m is an alkyl or aryl group; and X, Z, A ₁ , A ₂ and A ₃ are as defined herein.

  Compounds of the present invention having one or more asymmetric carbon atoms include optically pure enantiomers, pure diastereomers, enantiomeric mixtures, diastereomeric mixtures, enantiomeric racemic mixtures, diastereomeric racemates. Or a racemic mixture of diastereomers. It should be understood that the present invention contemplates all such isomers and mixtures thereof and is within the scope of the invention.

  In another embodiment of the invention, methods for synthesizing the novel compounds of the invention and methods for synthesizing intermediates useful in such methods are provided. Compounds of the present invention, Formula (I), Formula (II), Formula (III) and Formula (IV) can be synthesized by those skilled in the art according to the methods and examples described herein. It is. The reaction is carried out in a solvent suitable for the reactants, and the raw materials used are those suitable for proceeding with the conversion. Those skilled in organic synthesis will understand that the functional groups in the compound must be consistent with the desired chemical change. To this end, it may be necessary for the routine operator to determine the order of the synthesis steps, the required protecting groups and deprotection conditions, and the like. In some of the methods described, some of the required reaction conditions may be incompatible with the substituents attached to the starting materials, but those skilled in the art will recognize alternative methods and reaction conditions. It will be easy to find substituents that are consistent with The use of sulfur and oxygen protecting groups to protect thiol and alcohol groups to prevent undesired reactions in the synthesis procedure is known in the art and these are described in T.W. H. Green and P.I. G. M.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, New York (1991), the entire disclosure of which is hereby incorporated by reference. It is assumed that it is incorporated in the book.

  The above-mentioned chemical reactions are generally disclosed from the viewpoint of being most widely applicable for synthesizing the compounds of the present invention. In some cases, these reactions may not be applicable as described to individual compounds falling within the disclosed scope. Those skilled in the art will readily be able to identify the compounds in which this occurs. In such a case, conventionally employed modifications known to those skilled in the art, such as changing to another commonly used reactive agent that appropriately protects the interfering group, reacts in the normal range. It may be possible to proceed the reaction successfully by changing the conditions, etc., and the other reactions disclosed in the present specification or commonly used may be combined with the compounds involved in the present invention. It could also be applied to synthesize. In all synthetic methods, all starting materials are known or can be readily synthesized from known starting materials.

A nitroso compound of formula (I), wherein R _g and R _h are as defined herein, and 2 {4- [2- (nitrosooxy) ethyl] piperazinyl} ethane-1-ol are as defined herein. O-nitrosylated NSAID esters that are representative of the defined X group can be synthesized according to the following description. A suitable acid (ie, one in which X in formula (I) is substituted with hydroxy) is converted to an ester by reacting with a suitable diol with one group protected. As a preferred method of synthesizing the ester, the acid is first prepared in an anhydrous inert solvent such as dichloromethane, diethyl ether or THF in the presence of a non-nucleophilic base such as triethylamine, such as isobutyl chloroformate. React with chloroformate to form mixed anhydride. The mixed anhydride is then reacted with an alcohol with one group protected, preferably in the presence of a condensation reaction catalyst such as 4-dimethylaminopyridine. Alternatively, the acid may first be converted to the acid chloride by treatment with oxalyl chloride in the presence of a catalytic amount of DMF. The acid chloride is then reacted with an alcohol in which one group is protected, preferably in the presence of a condensation catalyst such as 4-dimethylaminopyridine and a tertiary amine base such as triethylamine to give the ester. Alternatively, the ester may be synthesized by coupling the acid and a diol with one group protected by treatment with a dehydrating agent such as DCC. Alternatively, the acid is first converted to an alkali metal salt such as sodium, potassium or lithium and reacted with an alkyl halide containing a protected hydroxy group in a polar solvent such as DMF to synthesize the ester. May be. As the protecting group for the alcohol moiety, a silyl ether such as trimethylsilyl ether or tert-butyldimethylsilyl ether is preferred. Deprotection of the hydroxyl site (preferably using a fluoride ion to remove the silyl ether protecting group) followed by thionyl chloride nitrite in a suitable anhydrous solvent such as dichloromethane, THF, DMF or acetonitrile. Reaction with a suitable nitrosylating agent such as thionyl dinitrite or nitrosium tetrafluoroborate provides compounds of formula (I).

A nitroso compound of formula (I), wherein R _g and R _h are as defined herein, and 2- {methyl [2-methyl-2- (nitrosothiol) propyl] amino} ethane-1-ol S-nitrosylated NSAID esters that are representative of the X group defined herein can be synthesized according to the following description. A suitable acid (ie, X in formula (I) substituted with hydroxy) is converted to an ester by reaction with a suitable protected thiol-containing alcohol. A preferred method for synthesizing the ester is to first react the acid with a chloroformate such as isobutyl chloroformate in an anhydrous inert solvent such as diethyl ether or THF in the presence of a non-nucleophilic base such as triethylamine. React with mate to form mixed anhydride. This mixed anhydride is then reacted with a protected thiol-containing alcohol, preferably in the presence of a condensation reaction catalyst such as 4-dimethylaminopyridine. Alternatively, the acid may first be converted to the acid chloride by treatment with oxalyl chloride in the presence of a catalytic amount of DMF. The acid chloride is then reacted with a protected thiol-containing alcohol, preferably in the presence of a condensation catalyst such as 4-dimethylaminopyridine and a tertiary amine base such as triethylamine to give the ester. Alternatively, the ester may be synthesized by combining a suitable acid and a protected thiol-containing alcohol by treatment with a dehydrating agent such as DCC. Alternatively, the acid is first converted to an alkali metal salt such as sodium, potassium or lithium, then reacted with an alkyl halide containing a protected thiol group in a polar solvent such as DMF to synthesize the ester. May be. Preferred protecting groups for the thiol moiety are thioesters such as thioacetate or thiobenzoate, disulfides, thiocarbamates such as N-methoxymethylthiocarbamate, or paramethoxybenzylthioether, tetrahydropyranylthioether or S- A thioether such as triphenylmethylthioether. Deprotection of the thiol site (dilute aqueous zinc acid, aqueous triphenylphosphine, and sodium borohydride are preferred to reduce disulfide groups, while bases are used to hydrolyze thioesters and N-methoxymethylthiocarbamate. An aqueous solution is usually used, and in order to remove the paramethoxybenzylthioether, tetrahydropyranylthioether, or S-triphenylmethylthioether group, strong acid and heat such as mercury trifluoroacetate, silver nitrate, trifluoroacetic acid or hydrochloric acid are used. And then in a suitable anhydrous solvent such as methylene chloride, THF, DMF or acetonitrile, thionyl chloride, thionyl dinitrate, lower alkyl nitrite such as tert-butyl nitrite, Or tetrafluorophor Is reacted with a suitable nitrosylating agent such as an acid Nitoroshiumu, compounds of formula (I) is obtained. As an alternative, the compound of formula (I) can also be obtained by treatment with a stoichiometric amount of sodium nitrite in an acidic aqueous solution.

A nitroso compound of formula (II), wherein R _k is as defined herein, and 2- {methyl [2-methyl-2- (nitrosothiol) propyl] amino} ethane-1-ol are as defined herein. S-nitrosylated NSAID esters that are representative of the X group defined in can be synthesized according to the following description. A suitable acid (ie, X in formula (II) substituted with hydroxy) is converted to an ester by reacting with a suitable protected thiol-containing alcohol. A preferred method for synthesizing the ester is to first react the acid with a chloroformate such as isobutyl chloroformate in an anhydrous inert solvent such as diethyl ether or THF in the presence of a non-nucleophilic base such as triethylamine. React with mate to form mixed anhydride. This mixed anhydride is then reacted with a protected thiol-containing alcohol, preferably in the presence of a condensation reaction catalyst such as 4-dimethylaminopyridine. Alternatively, the acid may first be converted to the acid chloride by treatment with oxalyl chloride in the presence of a catalytic amount of DMF. The acid chloride is then reacted with a protected thiol-containing alcohol, preferably in the presence of a condensation catalyst such as 4-dimethylaminopyridine and a tertiary amine base such as triethylamine to give the ester. Alternatively, the ester may be synthesized by combining a suitable acid and a protected thiol-containing alcohol by treatment with a dehydrating agent such as DCC. Alternatively, the acid is first converted to an alkali metal salt such as sodium, potassium or lithium, then reacted with an alkyl halide containing a protected thiol group in a polar solvent such as DMF to synthesize the ester. May be. Preferred protecting groups for the thiol moiety are thioesters such as thioacetate or thiobenzoate, disulfides, thiocarbamates such as N-methoxymethylthiocarbamate, or paramethoxybenzylthioether, tetrahydropyranylthioether or S- A thioether such as triphenylmethylthioether. Deprotection of the thiol site (dilute aqueous zinc acid, aqueous triphenylphosphine, and sodium borohydride are preferred to reduce disulfide groups, while bases are used to hydrolyze thioesters and N-methoxymethylthiocarbamate. An aqueous solution is usually used, and in order to remove the paramethoxybenzylthioether, tetrahydropyranylthioether, or S-triphenylmethylthioether group, strong acid and heat such as mercury trifluoroacetate, silver nitrate, trifluoroacetic acid or hydrochloric acid are used. And then in a suitable anhydrous solvent such as methylene chloride, THF, DMF or acetonitrile, thionyl chloride, thionyl dinitrate, lower alkyl nitrite such as tert-butyl nitrite, Or tetrafluorophor Is reacted with a suitable nitrosylating agent such as an acid Nitoroshiumu, compounds of formula (II) is obtained. As an alternative, the compound of formula (II) can also be obtained by treatment with a stoichiometric amount of sodium nitrite in an acidic aqueous solution.

A nitroso compound of formula (II), where R _k is as defined herein, and 2 {4- [2- (nitrosooxy) ethyl] piperazinyl} ethan-1-ol are defined herein. O-nitrosylated NSAID esters that are representative of the X group can be synthesized according to the following description. A suitable acid (ie, X in formula (II) substituted with hydroxy) is converted to an ester by reacting with a suitable diol with one group protected. As a preferred method of synthesizing the ester, the acid is first prepared in an anhydrous inert solvent such as dichloromethane, diethyl ether or THF in the presence of a non-nucleophilic base such as triethylamine, such as isobutyl chloroformate. React with chloroformate to form mixed anhydride. The mixed anhydride is then reacted with an alcohol with one group protected, preferably in the presence of a condensation reaction catalyst such as 4-dimethylaminopyridine. Alternatively, the acid may first be converted to the acid chloride by treatment with oxalyl chloride in the presence of a catalytic amount of DMF. The acid chloride is then reacted with an alcohol in which one group is protected, preferably in the presence of a condensation catalyst such as 4-dimethylaminopyridine and a tertiary amine base such as triethylamine to give the ester. Alternatively, the ester may be synthesized by coupling the acid and a diol with one group protected by treatment with a dehydrating agent such as DCC. Alternatively, the acid is first converted to an alkali metal salt such as sodium, potassium or lithium and reacted with an alkyl halide containing a protected hydroxy group in a polar solvent such as DMF to synthesize the ester. May be. As the protecting group for the alcohol moiety, a silyl ether such as trimethylsilyl ether or tert-butyldimethylsilyl ether is preferred. Deprotection of the hydroxyl site (preferably using a fluoride ion to remove the silyl ether protecting group) followed by thionyl chloride nitrite in a suitable anhydrous solvent such as dichloromethane, THF, DMF or acetonitrile. Reaction with an appropriate nitrosylating agent such as thionyl dinitrite or nitrosium tetrafluoroborate provides compounds of formula (II).

A nitroso compound of formula (III), wherein A ₁ , A ₂ , A ₃ , R _i and Z are as defined herein, and 2- {methyl [2-methyl-2- (nitrosothiol) propyl] S-nitrosylated enol esters in which amino} acetyl is representative of the X group defined herein can be synthesized according to the following description. The enol-form β-ketoamide of formula (III) in which X is replaced with hydrogen is converted to an ester by reacting with an appropriate protected thiol-containing active acylating agent. As a preferred method of synthesizing the ester, the enol is reacted with a pre-formed acid chloride or symmetric anhydride of a protected thiol-containing acid. Preferred protecting groups for the thiol moiety are thioesters such as thioacetate or thiobenzoate, disulfides, thiocarbamates such as N-methoxymethylthiocarbamate, or paramethoxybenzylthioether, tetrahydropyranylthioether or S- A thioether such as triphenylmethylthioether. Deprotection of thiol sites (diluted aqueous zinc acid, aqueous triphenylphosphine, and sodium borohydride are preferred to reduce disulfide groups, while bases are used to hydrolyze thioesters and N-methoxymethylthiocarbamate. Aqueous solutions are usually used, and to remove the paramethoxybenzylthioether, tetrahydropyranylthioether, or S-triphenylmethylthioether group, a strong acid such as mercury trifluoroacetate, silver nitrate, trifluoroacetic acid or hydrochloric acid and heat And then in a suitable anhydrous solvent such as methylene chloride, THF, DMF or acetonitrile, in the presence or absence of an amine base such as pyridine or triethylamine, Thionyl nitrite, It is reacted with a suitable nitrosylating agent such as nitrous acid lower alkyl, such as acid tert- butyl or tetrafluoroborate Nitoroshiumu, a compound of formula (III) is obtained. As an alternative, the compound of formula (III) can also be obtained by treatment with a stoichiometric amount of sodium nitrite in an acidic aqueous solution.

A nitroso compound of formula (III), wherein A ₁ , A ₂ , A ₃ , R _i and Z are as defined herein, and 2- {methyl [2-methyl-2- (nitrosooxy) ethyl] O-nitrosylated enol esters in which amino} acetyl is representative of the X group defined herein can be synthesized according to the following description. The enol-form β-ketoamide of formula (III) in which X is replaced with hydrogen is converted to an ester by reacting with an appropriate protected alcohol-containing active acylating agent. As a preferred method of synthesizing the ester, the enol is reacted with a pre-formed acid chloride or symmetric anhydride of a protected alcohol-containing acid. As the protecting group for the alcohol moiety, a silyl ether such as trimethylsilyl ether or tert-butyldimethylsilyl ether is preferred. Deprotection of the hydroxyl site (preferably using a fluoride ion to remove the silyl ether protecting group) followed by methylene chloride, THF in the presence or absence of an amine base such as pyridine or triethylamine. Suitable nitrosylation, such as thionyl chloride, thionyl dinitrate, lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as DMF or acetonitrile When reacted with an agent, a compound of formula (III) is obtained.

A nitroso compound of formula (IV) wherein A ₁ , A ₂ , A ₃ , R _m and Z are as defined herein, and 2- {methyl [2-methyl-2- (nitrosothiol) propyl] S-nitrosylated enol esters in which amino} acetyl is representative of the X group defined herein can be synthesized according to the following description. The enol-form β-ketoamide of formula (IV) where X is replaced with hydrogen is converted to an ester by reacting with an appropriate protected thiol-containing active acylating agent. As a preferred method of synthesizing the ester, the enol is reacted with a pre-formed acid chloride or symmetric anhydride of a protected thiol-containing acid. Preferred protecting groups for the thiol moiety are thioesters such as thioacetate or thiobenzoate, disulfides, thiocarbamates such as N-methoxymethylthiocarbamate, or paramethoxybenzylthioether, tetrahydropyranylthioether or S- A thioether such as triphenylmethylthioether. Deprotection of thiol sites (diluted aqueous zinc acid, aqueous triphenylphosphine, and sodium borohydride are preferred to reduce disulfide groups, while bases are used to hydrolyze thioesters and N-methoxymethylthiocarbamate. Aqueous solutions are usually used, and to remove the paramethoxybenzylthioether, tetrahydropyranylthioether, or S-triphenylmethylthioether group, a strong acid such as mercury trifluoroacetate, silver nitrate, trifluoroacetic acid or hydrochloric acid and heat And then in a suitable anhydrous solvent such as methylene chloride, THF, DMF or acetonitrile, in the presence or absence of an amine base such as pyridine or triethylamine, Thionyl nitrite, It is reacted with a suitable nitrosylating agent such as nitrous acid lower alkyl, such as acid tert- butyl or tetrafluoroborate Nitoroshiumu, a compound of formula (IV) is obtained. As an alternative, the compound of formula (IV) can also be obtained by treatment with a stoichiometric amount of sodium nitrite in an acidic aqueous solution.

A nitroso compound of formula (IV) wherein A ₁ , A ₂ , A ₃ , R _m and Z are as defined herein, and 2- {methyl [2-methyl-2- (nitrosooxy) ethyl] O-nitrosylated enol esters in which amino} acetyl is representative of the X group defined herein can be synthesized according to the following description. The enol-form β-ketoamide of formula (IV) in which X is replaced with hydrogen is converted to an ester by reacting with an appropriate protected alcohol-containing active acylating agent. As a preferred method of synthesizing the ester, the enol is reacted with a pre-formed acid chloride or symmetric anhydride of a protected alcohol-containing acid. As the protecting group for the alcohol moiety, a silyl ether such as trimethylsilyl ether or tert-butyldimethylsilyl ether is preferred. Deprotection of the hydroxyl site (preferably using a fluoride ion to remove the silyl ether protecting group) followed by methylene chloride, THF in the presence or absence of an amine base such as pyridine or triethylamine. Suitable nitrosylation, such as thionyl chloride, thionyl dinitrate, lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as DMF or acetonitrile When reacted with an agent, a compound of formula (IV) is obtained.

  The compounds of the present invention are NSAIDs, including those described herein, and nitroso via one or more active sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation), carbon and / or nitrogen. And / or nitrosylated. The nitrosated and / or nitrosylated NSAIDs of the present invention donate, transfer or release biologically active forms of nitric oxide (nitrogen oxide).

Nitric oxide can exist in three forms: NO ⁻ (nitroxyl), NO. (Uncharged nitric oxide) and NO ⁺ (nitrosonium). NO. Is a highly active and short-lived chemical species that is potentially toxic to cells. This is very important because the pharmacological efficacy of NO depends on its delivered form. In contrast to the nitric oxide radical (NO.), Nitrosonium (NO ⁺ ) does not react with O ₂ or O ₂ ⁻ species, and also has many functions to transfer and / or release NO ⁺ and NO ^−. Even if a redox metal is present, it is not easily damaged. As a result, administration of NO equivalents with a (plus and / or minus) charge is a more effective means of delivering biologically active NO to the desired site of action.

  Compounds used in the present invention (eg, nitrosated and / or nitrosylated NSAIDs) optionally release nitric oxide, and nitric oxide, or have an intended effect, such as a cell membrane in vivo. Used simultaneously with compounds that deliver or transfer biologically active forms of nitric oxide directly or indirectly to the site.

The term “nitrogen oxide” has a charge such as uncharged nitric oxide (NO.) And charged nitric oxide species, preferably nitrosonium ions (NO ⁺ ) and nitroxyl ions (NO ⁻ ). Includes nitric oxide species. The highly reactive form of nitric oxide can be donated as gaseous nitric oxide. A compound that releases, delivers, and transfers nitric oxide has the structure F-NO, where F is the site that releases, delivers, and transfers nitric oxide, and is active in a given form for a given purpose. This includes all compounds that give nitric oxide to the site of action. The term “NO adduct” encompasses all compounds that release, deliver, and transfer nitric oxide, including, for example, S-nitrosothiols, organic nitrites, organic nitrates, S-nitrothiols, sydnonimines, 2 -Hydroxy-2-nitrosohydrazine (NONOate), (E) -alkyl-2-[(E) -hydroxyimino] -5-nitro-3-hexenamine or amide, nitrosamine, furoxan, and nitrogen oxides Contains the endogenous enzyme substrate to be produced. “NO adducts” are mononitrosylated, polynitrosylated, mononitrosated and / or polynitrosated at various naturally acceptable or artificially provided biologically active forms of nitric oxide binding sites. Can be

  One group of NO adducts are S-nitrosothiols, which are compounds that contain at least one -S-NO group. These compounds include S-nitroso-polypeptides (the term “polypeptide” also includes proteins, polyamino acids whose biological function has not been identified and their derivatives); S-nitrosylated amino acids (natural and synthetic) Including amino acids, their stereoisomers, racemic mixtures and their derivatives); S-nitrosylated sugars; S-nitrosylated modified and unmodified oligonucleotides (preferably comprising at least 5, more preferably 5 to 200 nucleotides) ); Linear or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted S-nitrosylated hydrocarbons; and S-nitrosated heterocyclic compounds. US Pat. Nos. 5,380,758, 5,703,073, International Publication No. 97/27749, International Publication No. 98/19672, and Oae (S-nitrosothiols and methods for their production) Oae) et al., Org. Prep. Proc. Int. 15 (3): 165-198 (1983). The entire disclosures thereof are hereby incorporated by reference herein.

  Another embodiment of the present invention is an S-nitroso amino acid, wherein the nitroso group is attached to the sulfur group of the sulfur containing amino acid or derivative thereof. Such compounds include, for example, S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine, and S-nitroso. -Glutathione is included.

  Suitable S-nitrosylated proteins include thiol-containing proteins from various functional classes including enzymes such as tissue type plasminogen activator (TPA) and cathepsin B (NO group is amino acid or amino acid Attached to one or more sulfur groups of the derivatives); transport proteins such as lipoproteins; heme proteins such as hemoglobin and serum albumin; and biological defense proteins such as immunoglobulins, antibodies and cytokines. Such nitrosylated proteins are described in International Publication No. 93/09806, the entire disclosure of which is incorporated herein by reference. Examples include polynitrosylated albumin, in which one or more thiols or other nucleophilic centers of the protein are modified.

Other suitable S-nitrosothiols include the following.
(I) HS [C (R _e ) (R _f )] _m SNO;
(Ii) ONS [C (R _e ) (R _f )] _m R _e ; and (iii) H ₂ N—CH (CO ₂ H) — (CH ₂ ) _m —C (O) NH—CH (CH _{2 SNO) -C (O) NH-} CH 2 -CO 2 H;
Where m is an integer from 2 to 20; R _e and R _f are each independently hydrogen, alkyl, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, aryl heterocyclic ring, alkylaryl, cyclo Alkylalkyl, heterocyclic alkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, haloalkoxy, sulfonic acid, alkylsulfonic acid, arylsulfonic acid, arylalkoxy , Alkylthio, arylthio, cyano, aminoalkyl, aminoaryl, alkoxy, aryl, arylalkyl, alkylaryl, carboxamide, alkylcarboxa , Aryl carboxamide, amidyl, carboxyl, carbamoyl, alkyl carboxylic acid, aryl carboxylic acid, ester, carboxylic acid ester, alkyl carboxylic acid ester, aryl carboxylic acid ester, haloalkoxy, sulfonamide, alkyl sulfonamide, aryl sulfonamide, urea , Nitro, or —TQ; or R _e and R _f are bonded to each other to form a carbonyl group, a methanethiol, a heterocyclic ring, a cycloalkyl group, or a bridged cycloalkyl group; Is —NO or —NO ₂ ; and T is independently a covalent bond, oxygen, —S (O) _o — or N (R _a ) R _i , where o is an integer from 0 to 2 There, R _a is an electron lone pair, hydrogen or an alkyl group; and R _i is water , Alkyl, aryl, alkylcarboxylic acid, arylcarboxylic acid, alkylcarboxylic acid ester, arylcarboxylic acid ester, alkylcarboxamide, arylcarboxamide, alkylaryl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, sulfonamide, carboxamide, carvone Acid ester, aminoalkyl, aminoaryl, —CH ₂ —C (TQ) (R _e ) (R _f ), or — (N ₂ O ₂ —) ⁻ · M ⁺ , where M ⁺ is An organic or inorganic cation; provided that R _i is —CH ₂ —C (TQ) (R _e ) (R _f ) or — (N ₂ O ₂ —) · M ⁺ TQ] represents hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group. It may be a group or an aryl group.

In the case where R _e and R _f are a heterocyclic ring, or R _e and R _f are bonded to each other to form a heterocyclic ring, R _i is as defined in the present invention, and a radical It may be a substituent in any disubstituted nitrogen contained inside.

Nitrosothiol can be obtained by various synthetic methods. In general, the thiol precursor is first synthesized, then the thiol group is nitrosated with NaNO ₂ under acidic conditions (pH about 2.5) to convert to the S-nitrosothiol derivative, from which the S-nitroso derivative is converted. Synthesize. The acid used for this purpose is an aqueous solution of sulfuric acid, acetic acid and hydrochloric acid. Thiol precursors can also be nitrosylated by reaction with an organic nitrite such as tert-butyl nitrite or a nitrosonium salt such as nitrosonium tetrafluoroborate in an inert solvent.

  In another group of NO adducts used in the present invention, the compound in which the NO adduct donates, transfers or releases nitric oxide includes at least one ON-O-, ON-N- or ON-C- group There are compounds having Preferred compounds having at least one ON-O-, ON-N- or ON-C- group include ON-O-, ON-N- or ON-C-polypeptides (the term "polypeptide" Includes proteins, reamino acids with unidentified biological functions and derivatives thereof; ON-O-, ON-N- or ON-C-amino acids (natural and synthetic amino acids, their stereoisomers, racemic ON-O-, ON-N- or ON-C-sugars; ON-O-, ON-N- or ON-C-modified or unmodified oligonucleotides (at least 5 nucleotides, preferably 5) Linear or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted ON-O-, ON-N- or O -C- hydrocarbons; and, ON-O-, include ON-N-or ON-C-heterocyclic compound.

Another group of NO adducts used in the present invention are nitrate esters that donate, transfer or release nitric oxide, such as at least one of O ₂ N—O—, O ₂ N—N—, O It is a compound having a ₂ N—S— or O ₂ N—C— group. Among these compounds, preferred are O ₂ N—O—, O ₂ N—N—, O ₂ N—S— or O ₂ N—C-polypeptide (the term “polypeptide” refers to protein, biology) Including polyamino acids and their derivatives whose functional function has not been confirmed); O ₂ N—O—, O ₂ N—N—, O ₂ N—S— or O ₂ N—C-amino acids (natural and synthetic amino acids) , Their stereoisomers, including racemic mixtures); O ₂ N—O—, O ₂ N—N—, O ₂ N—S— or O ₂ N—C—sugars; O ₂ N—O—, O ₂ N-N-, O ₂ NS- or O ₂ N-C-modified and unmodified oligonucleotides (including at least 5 nucleotides, preferably 5 to 200 nucleotides); linear or branched, saturated Or unsaturated, aliphatic or aromatic, Or unsubstituted _{O 2 N-O-, O 2} N-N-, O 2 N-S- or _O 2 N-C- hydrocarbon; _{and, O 2 N-O-, O} 2 N-N-, O ₂ N—S— or O ₂ N—C—heterocyclic compound. Preferred compounds having at least one O ₂ N—O—, O ₂ N—N—, O ₂ N—S— or O ₂ N—C— group include isosorbide dinitrate, isosorbide mononitrate, and clonlate Erythrityl tetranitrate, mannitol hexanitrate, nitroglycerin, pentaerythritol tetranitrate, pentrinitrol and propatyl nitrate.

Another group of NO adducts is N-oxo-N-nitrosamine, which donates, transfers or releases nitric oxide and has the formula R ¹ R ² —N (OM ⁺ ) — NO. Where R ¹ and R ² are each independently a polypeptide, amino acid, sugar, modified or unmodified oligonucleotide, linear or branched, saturated or unsaturated, aliphatic or aromatic A substituted or unsubstituted hydrocarbon, or a heterocyclic group, where M ⁺ is an organic or inorganic cation such as, for example, an alkyl-substituted ammonium cation or a Group I metal cation.

Another group of NO adducts is thionitrate, which donates, transfers or releases nitric oxide and is represented by the formula R ^1- (S) -NO ₂ , where R ¹ is a polypeptide An amino acid, sugar, modified or unmodified oligonucleotide, linear or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or heterocyclic group. Preferred compounds are those in which R ¹ is a polypeptide or a hydrocarbon and the paired thiol is structurally close enough, ie, in a vicinal position, and the paired thiol is reduced to a disulfide. Is. Compounds that produce disulfide species release nitroxyl ions (NO ⁻ ) and uncharged nitric oxide (NO.). The compounds not near enough to the thiol group can form a disulfide bond, nitric oxide is generally NO ^- is released in the form of, it does not take the form of uncharged NO ·.

  The present invention is also directed to compounds that stimulate endogenous NO, increase the level of endothelium-derived relaxing factor (EDRF) in vivo, or serve as a substrate for nitric oxide synthase. Such compounds include, for example, L-arginine, L-homoarginine and N-hydroxy-L-arginine and their nitrosated and nitrosylated analogs (eg, nitrosated L-arginine, nitrosylated L-arginine). Nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosated L-homoarginine, and nitrosylated L-homoarginine), precursors of L-arginine and / or physiologically acceptable These salts include, for example, citrulline, ornithine or glutamine, inhibitors of the arginase enzyme (eg N-hydroxy-L-arginine and 2 (S) -amino-6-boronohexanoic acid). ) And nitric oxide synthase substrate Cytokines, adenosine, bradykinin, calreticulin, bisacodyl, and the like phenolphthalein. EDRF is a vascular relaxing factor secreted by the endothelium but has proven to be nitric oxide (NO) or a closely related derivative (Palmer et al., Nature, 327: 524-526). (1987); Ignarro et al., Proc. Natl. Acad. Sci. USA, 84: 9265-9269 (1987)).

  The present invention is also based on the discovery that inflammation, pain and fever can be treated by administering therapeutically effective amounts of the compounds and compositions described herein. For example, a patient can be administered a therapeutically effective amount of at least one nitrosated and / or nitrosylated NSAID of the present invention. In other embodiments, a therapeutically effective amount of at least one nitrosated and / or nitrosylated NSAID, and nitric oxide is donated, transferred or released, or endogenous EDRF or nitric oxide. At least one compound that increases levels or is a substrate for nitric oxide synthase can be administered. These compounds can be administered separately or in the form of one composition.

  Another aspect of the present invention is to provide gastrointestinal, renal and other causes attributable to the use of non-steroidal anti-inflammatory drugs by administering to a patient in need thereof a therapeutically effective amount of a compound and / or composition of the present invention. To reduce and / or ameliorate toxicity (eg, renal toxicity). For example, a therapeutically effective amount of at least one nitrosated and / or nitrosylated NSAID, and optionally donating, transferring or releasing nitric oxide, or endogenous EDRF or nitric oxide At least one compound that is a substrate for nitric oxide synthase can be administered. Nitrosated and / or nitrosylated NSAIDs and nitric oxide donors can be administered separately or as components of the same composition.

  Another aspect of the present invention provides a method for reducing and / or preventing gastrointestinal disorders by administering to a patient in need thereof a therapeutically effective amount of a compound and / or composition of the present invention. For example, a therapeutically effective amount of at least one nitrosated and / or nitrosylated NSAID, and optionally donating, transferring or releasing nitric oxide, or endogenous EDRF or nitric oxide At least one compound that is a substrate for nitric oxide synthase can be administered. Nitrosated and / or nitrosylated NSAIDs and nitric oxide donors can be administered separately or as components of the same composition. Such gastrointestinal disorders include, for example, peptic ulcer, stress ulcer, hyperacidity, dyspepsia, gastric paresis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, short bowel (anastomosis) syndrome, or systemic mastocytosis Or hypersecretory conditions associated with basophilic leukemia and hyperhistamine, and hemorrhagic peptic ulcers resulting from, for example, neurosurgery, head injury, severe physical trauma or burns.

  Another aspect of the invention requires treatment with a therapeutically effective amount of at least one nitrosated and / or nitrosylated non-steroidal anti-inflammatory compound and optionally at least one nitrogen donor. Methods of treating inflammatory disease states and disorders are provided by administering to a patient. Such inflammatory disease states and disorders include, for example, reperfusion injury to ischemic organs (eg, reperfusion injury to ischemic myocardium), myocardial infarction, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis , Hypertension, psoriasis, organ transplant rejection, organ preservation, female or male sexual dysfunction, radiation-induced damage, asthma, atherosclerosis, thrombosis, platelet aggregation, restenosis, metastasis, influenza, incontinence, seizures, burns, Trauma, acute pancreatitis, pyelonephritis, hepatitis, autoimmune disease, immunodeficiency, senile dementia, insulin-dependent diabetes, disseminated intravascular coagulation, fat embolism, Alzheimer's disease, adult or infant respiratory disease, carcinogenesis or bleeding in newborns including. The compounds and compositions of the invention can also be administered in combination with other pharmaceutical agents used to treat these conditions.

  Another aspect of the invention requires treatment with a therapeutically effective amount of at least one nitrosated and / or nitrosylated non-steroidal anti-inflammatory compound and optionally at least one nitrogen donor. Methods are provided for treating and / or preventing ophthalmic diseases and disorders by administering to a patient. For example, a therapeutically effective amount of at least one nitrosated and / or nitrosylated NSAID, and optionally donating, transferring or releasing nitric oxide, or endogenous EDRF or nitric oxide At least one compound that is a substrate for nitric oxide synthase can be administered. Nitrosated and / or nitrosylated NSAIDs and nitric oxide donors can be administered separately or as components of the same composition. Such ophthalmic diseases and disorders include glaucoma, ophthalmitis and elevated intraocular pressure.

  When administered in vivo, the compounds and compositions of the invention can be administered in combination with a pharmaceutically acceptable carrier and in dosages as described herein. When the compounds and compositions of the invention are administered as a mixture of at least one nitrosated and / or nitrosylated NSAID and at least one nitric oxide donor, the particular condition being treated Can be used in combination with one or more additional compounds known to be effective. Nitric oxide donors and / or other additional compounds can be administered at the same time as, or after, or prior to administration of the nitrosated and / or nitrosylated NSAID.

  The compounds and compositions of the present invention can be administered in any manner that is feasible and effective drug delivery systems, such as oral, buccal mucosa, parenteral, inhalation spray, topical application, injection, Administered in dosage unit formulations containing non-toxic, pharmaceutically acceptable carriers, adjuvants and vehicles, as commonly used as desired, transdermally or enterally (eg using suppositories) However, it is not limited to these. Parenteral methods include subcutaneous injections, intravenous injections, intramuscular injections, sternum injections or infusion techniques.

Transdermal administration of the compound, as is known to those skilled in the art, involves placing the drug through the skin into the patient's systemic circulation and delivering the drug. For topical administration, transdermal administration such as transdermal patches or iontophoresis may be used. Other ingredients may be added to the transdermal patch. For example, in compositions and / or transdermal patches, one or more preservatives or bacteriostatic agents may be added, such as methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, and the like. However, it is not limited to these. Dosage forms for topical administration of the compounds and compositions of the present invention include creams, sprays, lotions, gels, ointments, eye drops, nasal drops, ear drops and the like. In such dosage forms, the composition of the present invention can be used, for example, 1% or 2% (wt / wt) benzyl alcohol as a preservative to form a white, smooth, uniform, clear cream or lotion. wt), wax having emulsifying action, glycerin, isopropyl palmitate, lactic acid, purified water and sorbitol solution. Further, the composition can contain polyethylene glycol 400. These include, for example, benzyl alcohol 2% (wt / wt) as a preservative, white petroleum, wax with emulsifying action and Tenox II (butylated hydroxyanisole, propyl gallate, citric acid, propylene to form an ointment Glycol).
Alternatively, a pad or roll woven with a dressing material such as gauze can be impregnated with a solution, lotion, cream, ointment or other form of the composition of the invention and used for topical application. The composition can also be applied topically using a transdermal system such as an acrylic base adhesive containing a resinous crosslinker impregnated with the composition and laminated to an impermeable backing. .

  Solid preparations for oral administration include capsules, tablets, effervescent tablets, chewable tablets, pills, powders, sachets, granules and gels. In such solid preparations, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Also, as usual, such dosage forms may contain a lubricant such as magnesium stearate as an additional substance in addition to the inert diluent. In the case of capsules, tablets, effervescent tablets and pills, the dosage form may contain a buffer. Soft gelatin capsules can be prepared from a mixture of an active compound or composition according to the invention and a vegetable oil. In hard gelatin capsules, solid powder carriers such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives of gelatin and the like can be combined with the active compound particles. Tablets and pills can be manufactured with enteric coatings.

  Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, and inert diluents commonly used in the industry, such as water, are used. Such compositions may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, flavoring agents and the like.

  For example, for the treatment of pediatric fever, suppositories for administering the compounds and compositions of the invention to the vagina or rectum are suitable non-irritating excipients such as cocoa butter or polyethylene glycol. Can be made by mixing with agents. These excipients are solid at room temperature but become liquid at rectal temperature and dissolve in the rectum to release the drug.

  Injectable preparations, for example injections suspended in a sterile aqueous or oily base, can be prepared by using known methods using suitable dispersing agents, wetting agents and / or suspending agents. it can. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a 1,3-butanediol solution. Water, Ringer's solution, or isotonic saline are used as vehicles or solvents accepted. Sterile fixed oils are also often used as solvents or suspending media.

  The compositions of the present invention may further comprise conventional excipients, i.e. pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral application that do not have a detrimental effect on the active compound. Suitable pharmaceutically acceptable carriers include, for example, water, salt solutions, alcohol, vegetable oils, polyethylene glycol, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, fragrance oil. , Fatty acid monoglycerides or diglycerides, petroleum ether fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone and the like. The preparation is sterilized and, if necessary, does not have a detrimental effect on the active compound, eg lubricants, preservatives, stabilizers, wetting agents, emulsifiers, osmotic salts, buffering agents, coloring agents, flavoring agents And / or adjuvants such as fragrances can be mixed. For parenteral application, particularly suitable vehicles consist of solutions, in particular oily or aqueous solutions, suspensions, emulsions or implants. Aqueous suspensions may contain substances that increase the viscosity of the suspension and include, for example, sodium carboxymethylcellulose, sorbitol and / or dextran. Optionally, the suspension may contain a stabilizer.

  If necessary, the composition may also contain minor amounts of wetting agents, emulsifying agents and / or pH buffering agents. The composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release or powder. The composition can be formulated as a suppository, with conventional binders and carriers such as triglycerides. Oral formulations can include standard carriers such as formulation grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate and the like.

  Various delivery systems are known and can be used to administer the compounds or compositions of the invention, including, for example, encapsulation in liposomes, microbubbles, emulsions, microparticles, microcapsules and the like.

  The bioavailability of the composition is enhanced by micronization using conventional methods such as grinding, milling, spray drying, etc. in the presence of appropriate adjuvants or drugs such as phospholipids or surfactants. be able to.

  The compounds and compositions of the invention can also be formulated as neutral or pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, for example, free amino groups such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, benzoic acid, fumaric acid, glutamic acid, lactic acid, malic acid, In combination with maleic acid, nitric acid, succinic acid, tartaric acid, p-toluenesulfonic acid, methanesulfonic acid, gluconic acid, etc., and free carboxyl groups such as sodium, potassium, ammonium, calcium, ferric hydroxide , Isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, and the like.

  The term “therapeutically effective amount” refers to an amount of nitrosated and / or nitrosylated NSAID and nitric oxide donor effective to achieve the intended purpose. It is within the skill of the art to determine the optimal range of effective amounts of each of the compounds and compositions, as they vary from individual patient to patient. Generally speaking, the usage for administering an effective amount of the composition, and adjusting that amount by one of ordinary skill in the art, is dependent on the patient's age, health status, physical condition, gender, weight, patient dysfunction. It varies depending on the degree, frequency of treatment, and the nature and extent of dysfunction or disease.

  In the prevention or treatment of a specific dysfunction or condition, the effective amount of a nitrosated and / or nitrosylated NSAID depends on the nature of the dysfunction or condition, and is Can be determined by technology. References include Goodman and Gilman (supra); The Physician's Desk Reference; Medical Economic Company, Oradel, New Jersey, 1995; and Dora Drug Facts and Comparisons. Inc. , St. Louis, Missouri, 1993. The exact amount to be used in the formulation will also depend on the route of administration, the severity of the dysfunction or disorder, and should be determined by the physician and patient's environment.

  The dosage of nitric oxide donor in the pharmaceutical composition can be about 0.1 to about 10 times the molar equivalent of NSAID. The usual daily dosage of NSAID is about 3 to about 40 mg / kg body weight, and the dosage of nitric oxide donor in the pharmaceutical composition is about 1 to about 500 mg / kg body weight per day, preferably about 1 To about 50 mg / kg body weight. Effective doses can be determined by extrapolating dose response curves obtained in in vitro or animal model studies, and for commercially available compositions, the amounts described in Physician's Desk Reference (supra) Equivalent or small number is sufficient.

  The present invention further includes a pharmaceutical composition of the present invention comprising one or more of the nitrosated and / or nitrosylated NSAIDs described herein and one or more of the NO donors described herein. There is also provided a pharmaceutical kit including one or more containers filled with one or more of the above components. Such kits may be accompanied by instructions in a manner stipulated by government authorities that regulate the manufacture, use, or sale of the medicinal product or biological product. It may also reflect that the manufacture, use or sale for administration has been approved by the authorities.

  The following non-limiting examples further illustrate the invention and enable those skilled in the art to make and use the invention. In each example, flash chromatography was performed on 40 micron silica gel (Baker).

Example 1: 2- [4-Methyl-4- (nitrosothio) piperidyl] ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate hydrochloride 1a. Phenylmethyl 2- (4-oxopiperidyl) acetate A suspension of 4-piperidone (10.0 g, 65.0 mmol) and bromobenzyl acetate (14.9 g, 65.2 mmol) in acetone (100 mL) with stirring. _in, was added K ₂ CO 3 and _{(9.0g) Et 3 N (9.1mL} , 65.2 mmol). The reaction mixture was stirred at room temperature for 2 days and then the solvent was evaporated. The residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The organic layer was collected and dried over Na ₂ SO ₄ . The solvent was evaporated to give the title compound (13.3 g, 53.8 mmol, 83%) as a cloudy oil. _{^{1 HNMR (300MHz, CDCl 3)}} δ7.33~7.37 (m, 5H), 5.18 (s, 2H), 3.42 (s, 2H), 2.91 (t, J = 6.1Hz , 4H), 2.50 (t, J = 6.1 Hz, 4H).

1b. Phenylmethyl 2- (6-aza-1-oxaspiro [2.5] oct-6-yl) acetate Sodium hydride (1.6 g, 66.7 mmol) was suspended in dimethyl sulfoxide (80 mL). Trimethylsulfoxonium iodide (14.7 g, 66.8 mmol) was added in several portions at room temperature. After stirring for 20-30 minutes, the mixture became homogeneous. The product of Example 1a (12.7 g, 51.4 mmol) in dimethyl sulfoxide (40 mL) was then added and the reaction mixture was heated to 60 ° C. for 1 hour. The reaction mixture was then cooled to room temperature, poured into water and extracted with EtOAc. The organic layer was collected and dried over Na ₂ SO ₄ . The solvent was evaporated to give the title compound (13.1 g, 50.1 mmol, 97%) as a cloudy oil.
¹ HNMR (300 MHz, CDCl ₃ ) δ 7.33 to 7.38 (m, 5H), 5.18 (s, 2H), 3.32 (s, 2H), 2.74 to 2.80 (m, 2H) ), 2.66 (s, 2H), 2.61 to 2.70 (m, 2H), 1.88 to 1.96 (m, 2H), 1.52 to 1.59 (m, 2H).

1c. Phenylmethyl 2- (6-aza-1-thiaspiro [2.5] oct-6-yl) acetate The product of Example 1b (5.35 g, 20.5 mmol) was dissolved in methanol (70 mL). Thiourea (1.72 g, 22.6 mmol) was added and the mixture was stirred at 40 ° C. for 3 hours and then at room temperature overnight. The solvent was evaporated and the residue was dissolved in EtOAc and washed twice with water. The EtOAc layer was dried over Na ₂ SO ₄ . The solvent was evaporated to give the title compound that was used without further purification (5.6 g, 20.2 mmol, 98%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.30-7.38 (m, 5H), 5.17 (s, 2H), 3.34 (s, 2H), 2.88-2.91 (m, 2H) ), 2.55 to 2.62 (m, 2H), 2.44 (s, 2H), 2.21 to 2.28 (m, 2H), 1.52 to 1.57 (m, 2H).

1d. 2- (4-Methyl-4-sulfanylpiperidyl) ethane-1-ol The product of Example 1c (5.32 g, 19.2 mmol) was added to ice-cold LiAlH (24.0 mL, 14.0 mmol in 1M tetrahydrofuran). Of 20 mL tetrahydrofuran was added dropwise. After completion of dropping, the solution was cooled and stirred for 30 minutes. Water was added dropwise to stop the reaction. 5% methanol / dichloromethane solution was added and the mixture was filtered through celite. The filtrate was concentrated to an oil and dissolved in ethanol (20 mL). HCl in ether was added to precipitate the salt, which was filtered and washed thoroughly with ether to remove traces of benzyl alcohol. The amine was liberated by adding 10% ammonium hydroxide and then extracted with EtOAc. The organic extracts were collected and dried over Na ₂ SO ₄ . The solvent was evaporated to give the title compound as a clear oil (2.1 g, 12.0 mmol, 62%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.60 (t, J = 5.4 Hz, 2H), 2.45 to 2.67 (m, 4H), 2.57 (t, J = 5.4 Hz, 2H) 1.64-1.76 (m, 4H), 1.46 (s, 3H).

1e. 2- (4-Methyl-4-sulfanylpiperidyl) ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate The product of Example 1d (362 mg, 2.07 mmol), (2-(( To a mixture of 2,6-dichlorophenyl) amino) benzene) acetic acid (797 mg, 2.69 mmol) and dimethylaminopiperidine (126 mg, 1.03 mmol) in dichloromethane (20 mL) was added dicyclohexylcarbodiimide (555 mg, 2.69 mmol). Added at once. After about 5 minutes, a white precipitate began to form. The reaction was stirred for 3 hours. Ethanol was added to the mixture and filtered to remove solids. The solvent was evaporated. The residue was chromatographed on silica gel eluting with 1: 1 EtOAc: hexanes to give the title compound as a clear oil (287 mg, 0.63 mmol, 31%). ¹ HNMR (300 MHz, CDCl ₃ free base) δ 7.33-7.35 (m, 2H), 7.21-7.26 (m, 1H), 7.09-7.14 (m, 1H), 6 .89 to 7.00 (m, 3H), 6.53 to 6.56 (m, 1H), 4.27 (t, J = 5.9 Hz, 2H), 3.82 (s, 2H), 2 .67 (t, J = 5.9 Hz, 2H), 2.56 to 2.62 (m, 2H), 2.39 to 2.48 (m, 2H), 1.64 to 1.67 (m, 4H), 1.60 (s, 1H), 1.39 (s, 3H).

1f. 2- [4-Methyl-4- (nitrosothio) piperidyl] ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate The product of Example 1e (287 mg, 0.63 mmol) dissolved in ether HCl in ether was added dropwise. The white solid thus formed was collected, washed thoroughly with ether and dried in vacuo to give the HCl salt as a white solid (270 mg, 0.55 mmol). This salt (200 mg, 0.41 mmol) was dissolved in dichloromethane (4 mL). The solution was cooled to -78 ° C. t-Butyl nitrate (54 μL, 0.41 mmol) was added. The cooling bath was removed. After 10 minutes, the solvent was evaporated to give a green solid that was converted to the free amine by treatment with saturated aqueous K ₂ CO ₃ and extracted with EtOAc. The EtOAc extracts were collected and dried over Na ₂ SO ₄ . The solvent was evaporated and the crude was chromatographed on silica gel eluting with 1: 1 EtOAc: hexanes to give the title compound as a turbid oil (135 mg, 0.28 mmol, 69%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.33-7.36 (m, 2H), 7.21-7.24 (m, 1H), 7.08-7.14 (m, 1H), 6.88 To 7.01 (m, 3H), 6.53 to 6.56 (m, 1H), 4.29 (t, J = 5.8 Hz, 2H), 3.82 (s, 2H), 2.66 ˜2.76 (m, 2H), 2.68 (t, J = 5.8 Hz, 2H), 2.33 to 2.40 (m, 2H), 2.08 to 2.17 (m, 2H) 1.94 (s, 3H).

1g. 2- [4-Methyl-4- (nitrosothio) piperidyl] ethyl 2 {2-[(2,6-dichlorophenyl) amino] phenyl} acetate hydrochloride The product of Example 1f (130 mg, 0.27 mmol) in ether Dissolved and HCl in ether was added dropwise. The green solid thus formed was collected on a Buchner funnel and washed thoroughly with ether. The solid was dried in vacuo to give the title compound (127 mg, 0.24 mmol) as a green solid. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.36-7.43 (m, 2H), 7.16-7.19 (m, 1H), 7.00-7.08 (m, 2H), 6.83 To 6.87 (m, 1H), 6.41 to 6.44 (m, 1H), 4.72 to 4.75 (m, 2H), 3.86 (s, 2H), 3.38 to 3 .47 (m, 2H), 3.20 to 3.22 (m, 2H), 2.92 to 3.03 (m, 2H), 2.45 to 2.66 (m, 4H), 2.03 (S, 2H).

Example 2: 2- (Methyl {[(nitrosothio) cyclohexyl] methyl} amino) ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate hydrochloride 2a. 1-[(Formylcyclohexyl) disulfanyl] cyclohexanecarbaldehyde To a stirred solution of cyclohexanecarbaldehyde (100 g, 89 mmol) in carbon tetrachloride (100 mL) at 50 ° C. sulfur monochloride (36.4 mL, 91 mmol). ) Was added dropwise. After leaving for a short time (15 minutes), the evolution of HCl gas began. After outgassing ceased, the mixture was stirred at 55 ° C. for 1 hour and then cooled to room temperature. CCl ₄ was evaporated to give a yellow solid that was washed in a sintered glass funnel and washed with hexane (3 × 100 mL) to give the title compound as a white solid (114 g, 89%). . Melting point 85 to 88 ° C .; ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.24 to 1.33 (m, 6H), 1.42 to 1.46 (m, 6H), 1.62 to 1.69 (m, 4H), 1.94 to 1.99 (m, 4H), 8.94 (s, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 23.0, 25.1, 30.3, 60.8, 194 .3; Anal. Calcd for C ₁₄ H ₂₂ O ₂ S ₂ ; C, 58.70; H, 7.74; S, 22.38. Observed; C, 58.74; H, 7.69; S, 22.18.

2b. 2-[({[({[(2-hydroxyethyl) amino] methyl} cyclohexyl) disulfanyl] cyclohexyl} methyl) amino] ethane-1-ol The product of Example 2a in anhydrous CHCl ₃ (100 mL) (10 g , 34.91 mmol), ethanolamine (4.26 g, 69.82 mmol) and MgSO ₄ (10 g) were heated at reflux for 8 hours. The solid was filtered and the solvent was evaporated under reduced pressure to give a viscous yellow liquid. The crude product was dissolved in methanol (125 mL) and NaBH ₄ (3.3 g, 87.25 mmol) was added in portions over 10 minutes. The resulting solution was stirred at room temperature for 1 hour. Methanol was evaporated and the crude material was partitioned between a mixture of water (200 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was collected, dried over Na ₂ SO ₄ and evaporated under reduced pressure to give a colorless viscous liquid. The product was further purified to form a white salt by dissolving in ether (50 mL) and adding HCl in ether dropwise. The salt was washed with ether (2 x 50 mL) then the solid was dissolved in water (100 mL). The aqueous layer was washed with ether and the ether layer was discarded. The aqueous layer was basified with 15% ammonium hydroxide (10 mL) to give a white suspension that was extracted with ethyl acetate (2 × 50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (12.2 g, 93%) as a viscous liquid. ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.20 to 1.95 (m, 20H), 2.66 (s, 4H), 2.78 (t, J = 5.2 Hz, 4H), 3.61 (t , J = 5.2 Hz, 4H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 22.7, 25.8, 34.3, 51.5, 54.7, 60.6, 68.2.

2c. 2-[({[({[(2-hydroxyethyl) methylamino] methyl} cyclohexyl) disulfanyl] cyclohexyl} methyl) methylamino] ethane-1-ol Under nitrogen, the product of Example 2b (12 .2 g, 32.4 mmol), a mixture of 38% formaldehyde (35 mL) and methanol (70 mL) was stirred at room temperature for 12 hours. The solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give an oil. The crude product was dissolved in methanol (120 mL) and NaBH ₄ (3.05 g, 80.6 mmol) was added in portions over 10 minutes. The resulting solution was stirred at room temperature for 1 hour. Methanol was evaporated and the crude product was dissolved in a mixture of water (200 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The organic layer was collected, dried over Na ₂ SO ₄ and evaporated under reduced pressure to give the title compound (11.6 g, 88.5%) as a colorless viscous liquid. The product solidified while still standing. Melting point 65-70 ° C. ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.23-1.65 (m, 20H), 2.34 (s, 6H), 2.59 (s, 4H), 2.65 (t, J = 5.3 Hz) , 4H), 3.60 (t, J = 5.3 Hz, 4H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 22.3, 25.6, 33.4, 44.2, 55.9, 59.2. _{, 61.7,67.4; C 20 H 40 N} 2 O 2 S 2 relating calcd; C, 59.36; H, 9.96 ; N, 6.92; S, 15.84. Observed; C, 59.05; H, 9.71; N, 6.61; S, 15.88.

2d. 2- {methyl [(sulfanylcyclohexyl) methyl] amino} ethane-1-ol The product of Example 2c (11.6 g, 28.66 mmol) in anhydrous tetrahydrofuran (100 mL) stirred at room temperature under nitrogen. ) To the solution was added dropwise a 1M tetrahydrofuran solution of lithium aluminum hydride (43 mL, 43 mmol). The resulting solution was stirred at room temperature for 1 hour. Excess lithium aluminum hydride was destroyed by careful addition of water (5 mL) and anhydrous NH ₄ Cl (2 g) dropwise. Ethyl acetate (100 mL) was added and the precipitate was filtered. The white precipitate was washed with 10% methanol in dichloromethane (2 x 50 mL). The filtrate was collected, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (9.2 g, 79%) as a viscous liquid. ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.05 to 1.25 (m, 2H), 1.45 to 1.85 (m, 8H), 2.34 (s, 3H), 2.50 (s, 2H) ), 2.64 (t, J = 5.4 Hz, 2H), 3.56 (t, J = 5.4 Hz, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 22.2, 25.9, 38. 2, 44.8, 52.2, 59.4, 62.1, 72.2.

2e. 2- {methyl [(sulfanylcyclohexyl) methyl] amino} ethyl-2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate Example 2d in stirred CH ₂ Cl ₂ (50 mL) Product (1.0 g, 4.91 mmol) and 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid (1.45 g, 4.91 mmol) to dicyclohexylcarbodiimide in CH ₂ Cl ₂ (40 mL). (1.21 g, 5.89 mmol) was added dropwise over 1 hour. The suspension was then stirred at room temperature for 2 hours. The precipitate was filtered, washed with CH ₂ Cl ₂ (2 × 20 mL) and the filtrate was concentrated. The crude product was triturated with hexane (2 x 25 mL) and hexane was evaporated to give a viscous oil. The crude product was dissolved in CH ₂ Cl ₂ (5 mL) and subjected to silica gel column chromatography packed with hexane eluting with 5% ethyl acetate in hexane to give the title compound (1.35 g, 57%). TLC R _f = 0.35 (hexane / ethyl acetate, 9: 1; KMnO ₄ brown) ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.15 to 1.18 (m, 1H), 1.29 to 1.80 ( m, 9H), 2.12 (bs, 1H), 2.42 (s, 3H), 2.52 (s, 2H), 2.86 (t, J = 5.9 Hz, 2H), 3.84. (S, 2H), 4.28 (t, J = 5.9 Hz, 2H), 6.56 (d, J = 7.9 Hz, 1H), 6.93 to 7.00 (m, 3H), 7 .14 (t, J = 6.7 Hz, 1H), 7.23 (d, J = 6.7 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H); ¹³ CNMR (75 MHz, CDCl ₃ ) δ 22.3, 25.9, 37.6, 38.6, 45.2, 52.2, 58.5, 60.2, 63.1, 72.1 , 118.1, 121.9, 123.9, 124.1, 127.8, 128.7, 129.3, 130.8, 137.7, 142.6, 172.2; mass spectrum (EI) 510 (M ⁺ ), 172 (100).

2f. 2- {Methyl [(sulfanylcyclohexyl) methyl] amino} ethyl-2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate hydrochloride A solution of the product of Example 2e in anhydrous ether (30 mL) to ether. Dissolved HCl was added dropwise to form an insoluble white viscous product. The ether was evaporated under reduced pressure to give a white foam which was triturated with hexane (25 mL) to give a white suspension. Hexane was evaporated under reduced pressure and the material was dried in vacuo for 12 hours to give the title compound (2.1 g) as a white powder. Melting point 113 ° C. ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.14 to 1.30 (m, 1H), 1.34 to 2.00 (m, 9H), 2.95 to 3.01 (m, 1H), 2.96 (D, J = 4.2 Hz, 3H), 3.30 (d, J = 13.5 Hz, 1H), 3.43 to 3.60 (m, 3H), 3.86 (s, 2H), 4 .66 to 4.82 (m, 2H), 6.51 to 6.54 (m, 2H), 6.94 (t, J = 7.4 Hz, 1H), 7.02 (t, J = 8. 0 Hz, 1H) 7.06 to 7.16 (m, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 11.66 (Bs, 1H).

2g. 2- (Methyl {[(nitrosothio) cyclohexyl] methyl} amino) ethyl-2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate The product of Example 2f stirring at −78 ° C. ( To a solution of 2.28 g, 4.42 mmol) in CH ₂ Cl ₂ (50 mL) was added tertiary butyl nitrate (0.46 g, 4.42 mmol). The cooling bath was removed and the green solution was stirred for 10 minutes and then concentrated under reduced pressure to give a green foam. The green foam was dissolved in ethyl acetate (25 mL) and washed with saturated K ₂ CO ₃ (10 mL) then water (25 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a green viscous oil. The crude product was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in hexanes to give the title compound (1.92 g, 85.2%) as a green viscous oil. TLC R _f = 0.47 (hexane / ethyl acetate, 9: 1; green) ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.25 to 1.70 (m, 6H), 2.05 to 2.14 (m, 2H), 2.35 to 2.44 (m, 2H), 2.37 (s, 3H), 2.81 (t, J = 5.9 Hz, 2H), 3.19 (s, 2H), 3 .80 (s, 2H), 4.21 (t, J = 5.9 Hz, 2H), 6.54 (d, J = 8.0 Hz, 1H), 6.90 to 6.99 (m, 3H) 7.08-7.13 (m, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H); ¹³ C NMR (75 MHz, CDCl _{3) δ22.2,25.6,34.0,38.6,45.0,58.4,63.0,64.4,69.0,118.2,12} .0,124.0,124.2,128.0,128.8,129.4,130.9,137.8,142.7,172.2.

2h. 2- (Methyl {[(nitrosothio) cyclohexyl] methyl} amino) ethyl-2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate hydrochloride Anhydrous ether of the product of Example 2g (1.8 g) HCl in ether was added dropwise to the (30 mL) solution to form an insoluble green viscous product. The ether was evaporated under reduced pressure to give a green foam which was triturated with hexane (25 mL) to give a green suspension. Hexane was evaporated under reduced pressure and the material was dried in vacuo for 12 hours to give the title compound (1.86 g) as a green powder. Melting point 105-107 ° C. dec; ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.50-1.90 (m, 6H), 2.52 (bs, 2H), 2.88 (s, 3H), 3.35 3.52 (m, 2H), 3.80 to 4.20 (m, 2H), 3.82 (s, 2H), 4.72 (bs, 2H), 6.52 (d, J = 7. 6 Hz, 2H), 6.92 (t, J = 7.3 Hz, 1H), 7.01 (t, J = 7.7 Hz, 1H), 7.09 to 7.22 (m, 2H), 7. 34 (d, J = 8.0Hz, 2H), 12.61 (bs, 1H); C 24 H 30 N 3 O 3 analysis calculated for _{S 1 Cl 3; C, 52.89} ; H, 5.58 N, 7.76; S, 5.86. Observed; C, 53.48; H, 6.04; N, 6.55; S, 6.35.

Example 3: 2- (Methyl {[(nitrosothio) cyclohexyl] methyl} amino) ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate hydrochloride 3a. 2- {Methyl [(sulfanylcyclohexyl) methyl] amino} ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate Stirred product of Example 2d (1.0 g, 4.91 mmol) , (S) -6-methoxy-α-methyl-2-naphthaleneacetic acid (1.41 g, 6.14 mmol) and dimethylaminopyridine (0.3 g, 2.45 mmol) in anhydrous CH ₂ Cl ₂ (150 mL). To the solution was added dicyclohexylcarbodiimide (1.26 g, 20.28 mmol). The suspension was then stirred at room temperature for 3 hours. The precipitate was filtered and washed with CH ₂ Cl ₂ (2 × 50 mL). The filtrate was concentrated. The crude product was chromatographed on silica gel eluting with 10% ethyl acetate in hexanes to give the title compound (1.2 g, 59%). TLC R _f = 0.34 (hexane / ethyl acetate, 9: 1; KMnO ₄ brown) ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.05-1.70 (m, 10H), 1.59 (d, J = 7.1 Hz, 3H), 2.05 (bs, 1H), 2.33 (s, 3H), 2.43 (s, 2H), 2.77 (t, J = 5.7 Hz, 2H), 3 .82-3.95 (m, 1H), 3.90 (s, 3H), 4.11-4.24 (m, 2H), 7.11-7.15 (m, 2H), 7.41 (D, J = 8.4 Hz, 1H), 7.67 to 7.71 (m, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 18.46, 22.32. 25.93, 37.59, 45 .05, 45.45, 52.19, 55.20, 58.33, 62.71, 72.00, 105.51, 118.87, 125.91, 126.17, 127.07, 128.86, 129.19, 133.63, 135.57, 157.54, 174.55.

3b. 2- {Methyl [(sulfanylcyclohexyl) methyl] amino} ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate hydrochloride An anhydrous ether (20 mL) of the product of Example 3a (1.2 g) ) HCl in ether was added dropwise to the solution to form an insoluble white viscous product. The ether was evaporated under reduced pressure to give a white foam which was triturated with hexane (25 mL) to give a white suspension. Hexane was evaporated under reduced pressure and the material was dried in vacuo for 12 hours to give the title compound (1.28 g) as a white powder. ¹ HNMR (300 MHz, CDCl ₃ ) δ 0.94 to 1.80 (m, 10H), 1.58 (d, J = 7.1 Hz, 3H), 2.73 (dd, J = 4.5, 12. 0 Hz, 3H), 2.98 (t, J = 12.1 Hz, 3H), 3.25 to 3.26 (m, 2H), 3.90 to 4.00 (m, 1H), 3.90 ( s, 3H), 4.40-4.80 (m, 2H), 7.08-7.18 (m, 2H), 7.30-7.37 (m, 1H), 7.60-7. 80 (m, 3H).

3c. 2- (Methyl {[(nitrosothio) cyclohexyl] methyl} amino) ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate Product of Example 3b stirred at room temperature under nitrogen Tertiary butyl nitrate was added to a solution of (0.82 g, 1.81 mmol) in CH ₂ Cl ₂ (10 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure to give a green foam which was dissolved in ethyl acetate (25 mL) and washed with K ₂ CO ₃ (10 mL) then water (25 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a green viscous oil. The crude product was purified by flash chromatography on silica gel eluting with 10% ethyl acetate in hexanes to give the title compound (0.774 g, 96%) as a green viscous oil. TLC R _f = 0.34 (hexane / ethyl acetate, 9: 1; green) ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.25 to 1.66 (m, 6H), 1.55 (d, J = 7. 1 Hz, 3H), 2.05 to 2.14 (m, 2H), 1.92 to 2.02 (m, 2H), 2.25 to 2.35 (m, 2H), 2.27 (s, 3H), 2.70 (t, J = 5.8 Hz, 2H), 3.06 (dd, J = 14.6, 17.19 Hz, 2H), 3.78-3.90 (m, 1H), 3.85 (s, 3H), 4.07 to 4.16 (m, 2H), 7.05 to 7.13 (m, 2H), 7.37 (dd, J = 1.6, 8.4 Hz) ^{, 1H), 7.63~7.68 (m,} 3H); 13 CNMR (75MHz, CDCl 3) δ18.4,22.0,25.4,32.4,44 7, 45.3, 55.0, 58.0, 62.4, 64.3, 68.5, 105.4, 118.8, 125.8, 126.0, 127.0, 128.8, 129.1, 133.6, 135.8, 157.5, 174.4.

3d. 2- (Methyl {[(nitrosothio) cyclohexyl] methyl} amino) ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate hydrochloride in anhydrous ether (30 mL) and CH ₂ Cl ₂ mixture HCl in ether was added dropwise to the product of Example 3c (0.4 g) to form an insoluble green suspension. The solvent was evaporated under reduced pressure to give a green foam, which was triturated with hexane (10 mL) to give a green precipitate. Hexane was evaporated under reduced pressure and the material was dried in vacuo for 12 hours to give the title compound (0.403 g) as a green powder. Melting point 85 to 88 ° C., 110 ° C. dec; ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.17 to 1.81 (m, 6H), 1.54 (d, J = 7.1, 3H), 2.02 2.82 (m, 4H), 2.66 (s, 3H), 3.31 to 4.00 (bm, 5H), 3.90 (s, 3H), 4.52 to 4.63 (bm, 2H), 7.07 to 7.15 (m, 2H), 7.25 to 7.33 (m, 1H), 7.56 to 7.66 (m, 3H), 12.04 (bs, 1H) .

Example 4: 3- (methyl {[(nitrosothio) cyclohexyl] methyl} amino) propyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate 4a. 3-[({[({[(3- (Hydroxypropyl) methylamino] methyl} cyclohexyl) disulfanyl] cyclohexyl} methyl) methylamino] propan-1-ol The product of Example 2a stirring at room temperature ( To a suspension of 30 g, 105 mmol) in methanol (150 mL) was added propanolamine (15.7 g, 209 mmol) in methanol (50 mL). The reactants gradually dissolved over 45 minutes to form a light brown solution. The reaction was monitored by TLC indicating complete consumption of starting material. Sodium borohydride (4 g, 105 mmol) was added in portions over 10 minutes and the reaction mixture was stirred at room temperature for 1 hour. 38% formaldehyde (120 mL) was added and the resulting cloudy solution was stirred at room temperature for 2 hours. The flask was placed in a freezer (−20 ° C.) for 12 hours. The clear solution was discarded, leaving a viscous precipitate. The residue was vigorously shaken with methanol (50 mL) to yield a solid. The solid was filtered, washed with methanol (50 mL) and dried in vacuo to give the title compound (34 g, 75.7%) as a white powder. Mp 65-66 ° C. ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.20 to 1.80 (multit, 24H), 2.92 (s, 4H), 3.06 (t, J = 5.3 Hz, 4H), 3.93 (t , J = 5.2 Hz, 4H), 4.39 (s, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ22. 60.9, 67.7, 86.9; calculated for C ₂₂ H ₄₀ N ₂ O ₂ S ₂ ; C, 61.64; H, 9.40; N, 6.53; S, 14. 96. Observed; C, 61.70; H, 9.62; N, 6.38; S, 14.64.

4b. 3- {Methyl [(sulfanylcyclohexyl) methyl] amino} propan-1-ol To a solution of lithium aluminum hydride (18 mL @ 1M, 18 mmol) stirred at room temperature under nitrogen in THF (25 mL) Of Example 4a (5.00 g, 11.66 mmol) was added dropwise. The resulting clear solution was stirred at room temperature for 3 hours. Excess LiAlH was destroyed by adding water (1 mL) dropwise. Ethyl acetate (100 mL) was added and the precipitate was filtered. The white precipitate was washed with 10% methanol in CH ₂ Cl ₂ (2 × 50 mL). The filtrate was collected, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (4.9 g, 97%) as a viscous liquid. ¹ HNMR (300 MHz, CDCl ₃ ) d: 1.11 to 1.78 (multit, 12H), 2.33 (s, 3H), 2.46 (s, 2H), 2.69 (t, J = 6) .3 Hz, 2H), 3.75 (t, J = 5.1 Hz, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 22.1, 25.8, 37.8, 44.5, 51.5, 60 .4, 63.5, 73.34.

4c. 3- (Methyl {[(nitrosothio) cyclohexyl] methyl} amino) propan-1-ol A drop of HCl dissolved in ether in a solution of the product of Example 4b (4.9 g, free base) in anhydrous ether (50 mL). Add in portions to form an insoluble viscous material. The ether was discarded and the residue was washed with ether (2 x 50 mL) and vacuum dried for 12 hours to give a viscous solid (4.8 g). This solid was dissolved in CH ₂ Cl ₂ (50 mL) and added dropwise to t-BuONO (2.43 g, 23.6 mmol) in CH ₂ Cl ₂ (10 mL) stirred at room temperature. The resulting green solution was stirred at room temperature for 30 minutes. The reaction mixture was washed with saturated K ₂ CO ₃ (10 mL) followed by water (50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (4.2 g, 87%) as a green viscous oil. TLC R _f = 0.23 (hexane / ethyl acetate, 1: 1; green) ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.45 to 1.80 (multit, 8H), 2.09 (dd, J = 11.1. 0 and 13.6 Hz, 2H), 2.38 (s, 3H), 2.53 (d, J = 14 Hz, 2H), 2.74 (t, J = 5.8 Hz, 2H), 3.24 ( s, 2H), 3.77 (t, J = 5.2 Hz, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 21.9, 25.3, 28.7, 34.3, 44.2, 60. 1, 63.1, 63.7, 69.7.

4d. 3- (Methyl {[(nitrosothio) cyclohexyl] methyl} amino) propyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate The product of Example 4c (4. 2 g, 17.04 mmol), diclofenac (5.30 g, 17.89 mmol) and DMAP (0.15 g) in anhydrous CH ₂ Cl ₂ (30 mL) were added to dicyclohexylcarbodiimide (30 mL) in CH ₂ Cl ₂ (30 mL). 4.4 g, 21.46 mmol) was added dropwise over 15 minutes. The suspension was then stirred at 0 ° C. for 30 minutes. The precipitate was filtered and washed with CH ₂ Cl ₂ (25 mL). The filtrate was concentrated at 40 ° C. Hexane (100 mL) was added and the precipitate was filtered. The filtrate was concentrated under reduced pressure to give a green oil. The oil was dissolved in ethyl acetate (10 mL) and methanol (40 mL) was added. The solution was filtered and the filtrate was gradually heated to 40 ° C. for 2 minutes and then placed at −20 ° C. overnight (12 hours). The formed green crystals were filtered and dried in vacuo for 6 hours to give the title compound (8.4 g, 94%) as green crystals. Melting point 58-60 ° C .; TLC R _f = 0.46 (hexane / ethyl acetate, 9: 1;) ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.40-1.77 (multit, 6H) 1.84 (p, J = 6.8 Hz, 2H), 2.08-2.18 (multit, 2H), 2.35 (s, 3H), 2.47 (d, J = 13.9 Hz, 2H), 2.58 ( t, J = 7.1 Hz, 2H), 3.16 (s, 2H), 3.85 (s, 2H), 4.22 (t, J = 6.4 Hz, 2H), 6.61 (d, J = 7.9 Hz, 1H), 6.97 to 7.05 (multit, 3H), 7.16 (t, J = 5.0 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H) ^{), 7.38 (d, J =} 8.0Hz, 2H); 13 CNMR (75MHz, CDCl 3) δ22.2,25.5,26 7, 34.2, 38.6, 44.5, 56.5, 63.2, 64.4, 68.9, 118.2, 121.9, 123.9, 124.3, 127.8, _{128.8,129.4,130.8,137.8,142.7,172.3; C 25 H 31 N 3} O 3 analysis calculated for _{S 1 Cl 2; C, 57.25} ; H, 5 .96; N, 8.01; S, 6.11; Cl, 13.52. Observed; C, 57.42; H, 5.99; N, 7.73; S, 5.91; Cl, 13.20.

Example 5: 4-({Methyl [2-methyl-2- (nitrosothio) propyl] amino} methyl) phenyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate hydrochloride 5a. 4-{[(2-Methyl-2-sulfanylpropyl) amino] methyl} phenol To a solution of warm 4-hydroxybenzaldehyde (8.90 g, 72.8 mmol) in CHCl ₃ (250 mL) was added 1-amino-2. - methyl-2-propanethiol hydrochloride (10.32 g, 72.8 mmol) was added and MgSO ₄ and (5 g). The mixture was stirred and refluxed for 3 hours under a nitrogen atmosphere. After cooling, the mixture was filtered to remove inorganic solids and the filtered solids were washed through MeOH (2 × 100 mL). The filtrate was evaporated to give product 5a (15 g, 98%) as a white solid. Mp 85-57 ° C. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.38 (d, J = 8.5 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H), 5.74 (s, 1H), 3.25 (D, J = 12.1 Hz, 1H), 3.01 (d, J = 12.1 Hz, 1H), 1.59 (s, 3H), 1.58 (s, 3H).

5b. N-[(4-hydroxyphenyl) methyl] methoxy-N- (2-methyl-2-sulfanylpropyl) carboxamide To a suspension of the product of Example 5a (700 mg, 3.35 mmol) in THF (80 mL) was added methyl. Chloroformate (518 mL, 6.70 mmol) and solid NaHCO ₃ (588 mg, 7.0 mmol) were added. The mixture was stirred at room temperature for 2 hours, at which time the reactants were completely consumed. The inorganic solid was removed by filtration and the filtrate was evaporated. The resulting crude product was purified by silica gel flash chromatography eluting with Hex: EtOAc = 1: 4 to give the title compound (877 mg, 98%) as a white snowflake. Melting point 51 ° C. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.49 (br, 1H), 7.19 (br, 2H), 6.70 (br, 2H), 6.14 (s, 1H), 4.1-4. 0 (br, 1H), 3.66 (s, 3H), 3.58 to 3.53 (m, 1H), 1.47 (s, 3H), 1.46 (s, 3H).

5c. 4-{[Methyl (2-methyl-2-sulfanylpropyl) amino] methyl} phenol To a stirred solution of Example 5b (5.00 g, 18.7 mmol) in THF (150 mL) was added lithium hydride. Ammonium (37.4 mL @ 1M, 37.4 mmol) was added dropwise. After the addition, the reaction mixture was heated and refluxed overnight. For cooling, the mixture was poured onto ice and extracted with ethyl acetate (2 x 150 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (3.44 g, 83%) as a colorless oil. ¹ HNMR (CDCl ₃ , 300 MHz) δ 7.20 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 5.30 (br, 1H), 3.60 (S, 2H), 2.54 (s, 2H), 2.28 (s, 3H), 2.05 (s, 1H), 1.35 (s, 6H); ¹³ C NMR (CDCl ₃ , 75 MHz) δ 154.8, 130.5, 129.8, 115.0, 70.5, 63.5, 46.2, 44.2, 30.2.

5d. 4-{[Methyl (2-methyl-2-sulfanylpropyl) amino] methyl} phenyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate The stirred product of Example 5c (1.92 g) , 7.18 mmol), (S)-6-methoxy--a- methyl-2- naphthaleneacetic acid (1.65 g, 7.18 mmol) and DMAP (0.88g, _{CH 2} Cl 2 of 7.18 mmol) To the (80 mL) solution was added dicyclohexylcarbodiimide (1.48 g, 7.18 mmol). The reaction mixture was stirred at room temperature for 2 hours under nitrogen. The white solid formed during the reaction was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 1: 5 ethyl acetate: hexanes to give the title compound (2.90 g, 90%) as a glassy solid. ¹ HNMR (CDCl ₃ , 300 MHz) δ 7.72 to 6.91 (m, 10H), 4.02 (q, J = 7.1 Hz, 1H), 3.74 (s, 3H), 3.51 (s , 2H), 2.42 (s, 2H), 2.16 (s, 3H), 2.06 (s, 1H), 1.63 (d, J = 7.1 Hz, 3H), 1.26 ( ^13C NMR (CDCl ₃ , 75 MHz) δ 172.7, 157.3, 149.3, 137.0, 134.8, 133.4, 129.0, 128.9, 128.5, 127 0.0, 125.7, 125.7, 120.7, 118.7, 105.2, 70.8, 63.4, 54.8, 46.1, 45.1, 44.2, 30.0 , 18.2.

5e. 4-({Methyl [2-methyl-2- (nitrosothio) propyl] amino} methyl) phenyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate hydrochloride with HCl in Et ₂ O The HCl salt of the product of Example 5d was prepared by treating the compound. Stirred solution of salt (1.34 g, 2.82 mmol) t-BuONO (90%, 0.391mL, 2.96 mmol) in _CH 2 _Cl 2 (40mL) solution of was added. The reaction mixture was stirred for 15 minutes at room temperature and then evaporated to dryness. The resulting green hydrochloride salt was converted to the free base by partitioning with ethyl acetate and 1M aqueous K ₂ CO ₃ solution. The organic layer was washed with water, dried over Na ₂ SO ₄ and evaporated. The residue was purified by silica gel flash chromatography eluting with ethyl acetate: hexane = 1: 4. The free base was purified by treatment with HCl-Et 2 _O and re-converted to hydrochloride salt. Trituration of the HCl salt with hexanes afforded the title compound (1.18 g, 83%) as a green amorphous solid. ¹ HNMR (CDCl ₃ , 300 MHz) δ 7.75-6.90 (m, 10H), 4.07 (q, J = 7.1 Hz, 1H), 3.89 (s, 3H) 3.59 (s, 2H), 3.11 (s, 2H), 2.23 (s, 3H), 1.85 (s, 6H), 1.67 (d, J = 7.1 Hz, 3H); ¹³ C NMR (CDCl ₃ 75MHz) δ 172.8, 157.3, 149.4, 134.8, 133.4, 129.1, 128.9, 127.0, 125.5, 120.9, 120.8, 118.8 105.2, 67.8, 63.4, 58.6, 55.0, 45.2, 44.3, 26.8, 25.9, 18.2.

Example 6: 2- [4- (Nitrosothio) -4-piperidyl] ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate hydrochloride 6a. Ethyl 2- {1-[(tertiarybutyl) oxycarbonyl] -4-piperidene} acetate A solution of triethylphosphonoacetate (8.9 mL, 45 mmol) in THF (50 mL) was cooled to -78 ° C. n-BuLi (18 mL@2.5 m, 45 mmol) was quickly added dropwise and the mixture was stirred for 30 minutes. T-Butyl 4-oxo-1-piperidinecarboxylate (9 g, 45 mmol) in THF (50 mL) was added and the mixture was kept at −78 ° C. for 1 hour. The cooling bath was removed and stirring was continued for 2 hours. The reaction was diluted with Et ₂ O (100 mL) and washed with NaHCO ₃ (1 × 50 mL). Extract the aqueous layer with Et ₂ O (50 mL). The organic layer was collected, washed with H ₂ O (1 × 30 mL), brine (1 × 50 mL) and dried over Na ₂ SO ₄ . Evaporation of the solvent gave the title compound that crystallized on standing. Mp 84-85 ° C. ¹ HNMR (300 MHz, CDCl ₃ ) δ 5.69 (s, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.44 to 3.50 (multit, 4H), 2.29 (t , J = 5.7 Hz, 2H), 2.26 (t, J = 5.8 Hz, 2H), 1.46 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H); C Analytical calculated for ₁₄ H ₂₃ NO ₄ ; C, 62.43; H, 8.61; N, 5.20. Observed; C, 61.92; H, 8.36; N, 5.89.

6b. Ethyl 2- {1-[(tertiarybutyl) oxycarbonyl] -4- (phenylmethylthio) -4-piperidyl} acetate The product of Example 6a (12 g, 45 mmol) and benzyl mercaptan (5.3 mL, 45 mmol) ) Was dissolved in piperidine (20 mL) and heated to reflux for 5 hours. Toluene (100 mL) was added and then the solvent was removed under reduced pressure leaving a cloudy syrup. The residue was dissolved in Et ₂ O (200 mL), washed with 1N HCl (1 × 50 mL), 0.5N NaOH (1 × 50 mL), brine (1 × 50 mL), and Na ₂ SO ₄ was dried. The solvent was evaporated to give the title compound (18 g, 100%) as an oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.23 to 7.32 (multit, 5H), 4.14 (q, J = 7.1 Hz, 2H), 3.72 (s, 2H), 3.70 to 3 .80 (multit, 2H), 3.30 (t, J = 12 Hz, 2H), 2.65 (s, 2H), 1.70 to 1.90 (multit, 4H), 1.46 (s, 9H) ), 1.26 (t, J = 7.1 Hz, 3H); ¹³ C NMR (75 MHz, d ₆ -DMSO) δ 169.6, 153.8, 137.6, 128.9, 126.8, 78.5 59.7, 46.8, 44.9, 41.8, 34.4, 30.9, 14.0.

6c. Tertiary butyl 4- (2-hydroxyethyl) -4- (phenylmethylthio) piperidinecarboxylate The product of Example 6b (1 g, 2.5 mmol) in THF (10 mL) was cooled to 0 ° C. Dibal-H (5.5 mL @ 1M, 5.5 mmol) was added and the reaction was stirred for 30 minutes. The cooling bath was removed and the mixture was stirred until the reaction was complete as determined by TLC. The reaction mixture was cooled to 0 ° C. and 1N HCl was added dropwise until the reaction became gelatinous, and 1N HCl was added rapidly until the gel dissolved when gelatinized. The mixture was transferred to a separatory funnel with Et ₂ O. 1N HCl was added as needed until two uniform layers were obtained. The layers were separated and the aqueous layer was extracted with Et ₂ O (2 × 10 mL). The organic layers were collected, washed with 1N HCl (1 × 10 mL), brine (1 × 10 mL) and dried over Na ₂ SO ₄ . The solvent was evaporated and the residue was chromatographed on silica gel eluting with hexane: ethyl acetate = 1: 1 to give the title compound (340 mg, 40%) as an oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.23 to 7.32 (multit, 5H), 3.76 (multit, 2H), 3.69 to 3.76 (multit, 2H), 3.69 (s, 2H) ), 3.32 (t, J = 11 Hz, 2H), 2.20 (brs, 1H), 1.88 (t, J = 6.4 Hz, 2H), 1.76 (d, J = 14 Hz, 2H) ), 1.52-1.61 (multit, 2H), 1.46 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 154.5, 137.3, 128.7, 128.3, 126. 9, 79.3, 58.4, 47.7, 42.2, 39.0, 35.3, 31.5, 28.2.

6d. Tertiary butyl 4- (2-hydroxyethyl) -4-sulfanylpiperidinecarboxylate Ammonia (20 mL) was concentrated in a 3-way flask fitted with a dry ice condenser. The product of Example 4c (340 mg, 1 mmol) was added to EtOH (4 mL), then sodium metal (76 mg, 33 mmol) was added until the blue color persisted. A small amount of NH ₄ Cl was added to quench the blue color and ammonia was evaporated with a stream of nitrogen gas. The residue was partitioned between Et ₂ O and 1N HCl. The aqueous layer was extracted with Et ₂ O (1 × 20 mL). The organic layer was collected, washed with brine (1 × 10 mL) and dried over Na ₂ SO ₄ . The solvent was evaporated to give the title compound (210 mg, 80%) as an oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.95 (t, J = 6.7 Hz, 2H), 3.80 to 3.90 (multit, 2H), 3.20 to 3.35 (multit, 2H), 1 .95 (t, J = 6.7 Hz, 2H), 1.60 to 1.80 (multit, 4H), 1.46 (s, 9H).

6e. Tertiary butyl 4- (2-hydroxyethyl) -4- (nitrosothio) piperidinecarboxylate The product of Example 6d (2.5 g, 9.5 mmol) was dissolved in CH ₂ Cl ₂ (50 mL) and 10 ° C. Cooled to. Tertiary butyl nitrate was added and stirring was continued for 30 minutes. The solvent was evaporated and the green residue was chromatographed on silica gel eluting with hexane: ethyl acetate = 1: 1. This gave the title compound (1 g, 35%) as a green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.83 (d, J = 12 Hz, 2H), 3.71 (t, J = 6 Hz, 2H), 2.99-3.12 (multit, 3H), 2.40 ~ 2.50 (multit, 4H), 2.06-2.16 (multit, 2H), 1.36 (s, 9H).

6f. 2- {1-[(tertiarybutyl) oxycarbonyl] -4- (nitrosothio) -4-piperidyl} ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate CH ₂ Cl ₂ ( To the product of Example 6e (1 g, 3.4 mmol) and {2-[(2,6-dichlorophenyl) amino] benzene} acetic acid (1.1 g, 3.4 mmol) in 10 mL) was added CH ₂ Cl _2. A mixture of dichlorohexylcarbodiimide (0.77 g, 4 mmol) and DMAP (10 mg, 0.08 mmol) in (10 mL) was added. The mixture was stirred at room temperature for 2 hours. The precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed on silica gel eluting with hexane: ethyl acetate = 4: 1 to give the title compound (1.4 g, 72%) as a green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.33 (d, J = 8 Hz, 2H), 7.19 (d, J = 7.4 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H) 6.92 to 6.99 (multit, 2H), 6.78 (s, 1H), 6.54 (d, J = 7.9 Hz, 1H), 4.36 (t, J = 6.7 Hz, 2H), 3.90 (brs, 2H), 3.77 (s, 2H), 2.69 (t, J = 6.7 Hz, 2H), 2.44 (t, J = 15 Hz, 2H), 2 .05 to 2.15 (multit, 2H), 1.47 (s, 9H).

6g. 2- [4- (Nitrosothio) -4-piperidyl] ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate hydrochloride CH ₂ Cl ₂ (2 mL) and Et ₂ O saturated with HCl ( 2 mL) was dissolved in the product of Example 6f and then allowed to stand at room temperature for 1.5 hours. Addition of Et ₂ O resulted in precipitation of green material. The supernatant was discarded. The residue was dissolved in CH ₂ Cl ₂ and precipitated with Et ₂ O. This was repeated twice more. The residue was then vacuum dried to give 6 g (0.95 g, 82%) of product as a green foam. ¹ HNMR (300 MHz, d6-DMSO) δ 9.25 (brs, 1H), 7.52 (d, J = 8 Hz, 2H), 7.15 to 7.23 (multit, 2H), 7.01 to 7. 08 (multit, 2H), 6.84 (t, J = 7.4 Hz, 1H), 6.23 (d, J = 7.9 Hz, 1H), 4.26 (t, J = 6.5 Hz, 2H) ), 3.77 (brs, 2H), 2.93 (t, J = 9 Hz, 2H), 2.59 to 2.69 (multit, 2H), 2.49 to 2.51 (multit, 4H). Mass spectrum _{^{(API-ES) MH + =}} 468; C 21 H 24 Cl 3 N 3 O 3 calcd about S; C, 49.96; H, 4.79; N, 8.32. Observed; C, 48.98; H, 5.06; N, 7.9.

Example 7: 2- [2- (2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetoxy) ethoxy] ethyl 3- (N-{[(nitrosothio) cyclohexyl] methyl} -N-benzyl Carbamoyl) propanoate 7a. The product of Example 2a (12.0 g, 41.89 mmol) and benzylamine (8.98 g, 83.8 mmol) in di [(benzylamino) methyl] cyclohexyl disulfide CHCl ₃ (150 mL) were heated to 3 Reflux for hours. After cooling to room temperature, the solvent was evaporated using a rotary evaporator. The residue was dissolved in MeOH (150 _mL), was added NaBH 4 the (3.17 g, 83.8 mmol) portionwise. After 1 hour, the solvent was evaporated and the residue was partitioned between water (200 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 100 mL). The organic layer was collected, dried over Na ₂ SO ₄ and evaporated to give the title compound. ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.30 to 1.74 (multit, 20H), 2.59 (s, 4H), 3.45 (s, 2H), 3.79 (s, 4H), 7. ^{22~7.32 (mult, 10H); 13} CNMR (75MHz, CDCl 3) δ22.23,25.80,34.36,54.01,54.63,56.42,126.78,128.00 128.25, 140.50.

7b. 1-[(Benzylamino) methyl] cyclohexane-1-thiol The product of Example 7a was dissolved in THF (100 mL) and LiAlH in THF (50 mL @ 1M, 50 mmol) was added. After stirring at room temperature for 2 hours, the reaction was stopped using the following protocol, water (1.9 mL), 15% sodium hydroxide (1.9 mL) and water (5.8 mL). The precipitate was removed by filtration and the solvent was evaporated. The residue was purified by flash chromatography (SiO _2, hexane / Et ₂ O 1: 5 to 1: 1) to give the title compound (11.05 g, 56%, 2 steps) and unreacted starting material ( 7.94 g, 40%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.20 to 1.75 (multit, 10H), 2.64 (s, 2H), 3.84 (s, 2H), 7.40 to 7.33 (multit, 5H) ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 22.23, 26.02, 38.08, 50.62, 54.15, 62.04, 126.78, 127.88, 128.26, 140.54.

7c. 3- (N-{[(Nitrosothio) cyclohexyl] methyl} -N-benzylcarbamoyl} propanoic acid 7b product (2.98 g, 12.66 mmol) in CH ₂ Cl ₂ (50 mL) in ice-cold solution and succinic anhydride (1.2 g, 12.6 mmol) was stirred at room temperature for 2 h, the reaction was diluted with CH ₂ Cl ₂ (50 mL) and washed with 2N hydrogen chloride (50 mL) and brine (50 mL). _The 2Cl ₂ solution was dried over Na ₂ SO ₄ and evaporated The residue was dissolved in CH ₂ Cl ₂ (100 mL) To this solution was added t-BuONO (1.53 mL, 13.09 mmol). .2 hours after the solution was washed with brine, dried over Na ₂ SO _4. the solvent was evaporated under reduced pressure to give a crude product, which was triturated with EtOAc / hexanes, green The title compound (7.30 g, 93.2%, 2 steps or more) was obtained as a solid of mp 93-95 ° C. ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.43-1.73 (multit, 6H) ), 2.13 (t, J = 1 1 Hz, 2H), 2.51 (d, J = 14.2 Hz, 2H), 2.59-2.75 (multit, 4H), 4.08 and 4.24. (2s, 2H), 4.56 and 4.81 (2s, 2H), 7.04 and 7.12 (2d, J = 7.1 Hz, 2H), 7.23 to 7.35 (multit, 3H) ¹³ C NMR (75 MHz, CDCl ₃ ) δ 21.9, 25.3, 28.3, 29.3, 34.9, 53.4, 56.5, 64.1, 125.9, 127.7, 129; 0.0, 136.1, 174.0, 177.9; mass spectrum (API-E ^{), M / z): 366} (M + +1); C 18 H 24 N Analysis Calculated for _{2 O 4 S; C, 59.32} ; H, 6.64; N, 7.69; S, 8. 80. Observed; C, 59.56; H, 6.83; N, 7.57; S, 8.77.

7d. 2- (2-hydroxyethoxy) ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid (2 To a suspension of anhydrous CHCl ₃ (0.0 g, 6.7 mmol), 1,1′-carbonyldiimidazole (1.37 g, 6.75 mmol) was added in portions. The resulting solution was stirred at room temperature for 30 minutes. CHCl ₃ (10 mL) solution of di (ethylene glycol) (2.30 g, 22.3 mmol) was added, at room temperature for 6 h, the solution was stirred. CHCl ₃ was evaporated under reduced pressure and the crude product was flash chromatographed on silica gel eluting with ethyl acetate / hexane (1: 2) to give the title compound (2.1 g, 81%) as a clear oil. Got. TLCR _f = 0.33 (EtOAc: Hex, 1: 2); ¹ HNMR (300 MHz, CDCl ₃ ) δ2.71 (brs, 1H), 3.44 (multit, 2H), 3.57 to 3.63 ( multit, 4H), 3.76 (s, 2H), 4.23 (t, J = 4.8 Hz, 2H), 6.46 (d, J = 8.0 Hz, 1H), 6.80-7. 01 (multit, 1H), 7.03 (multit, 1H), 7.15 (dd, J = 1.4 and 7.4 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 38.4, 61.6, 64.2, 68.8, 72.3, 118.1, 121.9, 124.0, 127.9, 128.8, 129. 4, 130.8, 137.6, 142.6, 172.3; mass spectrum API-ES), m / z384 (MH +).

7e. 2- [2- (2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetoxy) ethoxy] ethyl 3- (N-{[(nitrosothio) cyclohexyl] methyl} -N-benzylcarbamoyl) propanoate CH _To the product of Example 7c (0.41 g, 1.1 mmol), Example 7d (0.43 g, 1.1 mmol) and DMAP (0.025 g) in ₂ Cl ₂ (10 mL) at room temperature. Dicyclohexylcarbodiimide (0.28 g, 1.3 mmol) was added. The resulting suspension was stirred at room temperature for 1 hour. The precipitate was filtered and washed with CH ₂ Cl ₂ (25 mL). The filtrate was concentrated and the crude material was chromatographed on silica gel eluting with ethyl acetate / hexane (1: 9) to give the title compound (0.55 g, 67%) as a green oil. TLCR _f = 0.48 (EtOAc: Hex, 1: 2); ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.45 to 1.56 (multit, 3H), 1.70 to 1.74 (multit, 3H), 2.10 to 2.18 (multit, 2H), 2.50 to 2.69 (multit, 6H), 3.66 (t, J = 4.6 Hz, 2H), 3.72 (t, J = 4) .6 Hz, 2H), 3.86 (s, 2H), 4.21 to 4.38 (multit, 6H), 4.58 (s, 2H), 6.55 (d, J = 7.8 Hz, 1H) ), 6.97-7.30 (multit, 12H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 21.9, 25.3, 28.2, 29.2, 34.8, 38.4, 53.2 , 56.2, 63.5, 64.2, 68.8, 68.9, 118.1, 121. , 124.1, 125.1, 127.5, 127.9, 128.5, 128.7, 128.9, 129.3, 130.8, 136.2, 137.7, 142.6, 172 2, 172.7, 173.6; mass spectrum (API-ES), m / z 730 (MH ^<+> ), 700 (M ^<+>- 30, -NO).

Example 8: 2- {4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate citrate 8a. 2,2-Dimethylthiirane Isobutylene epoxide (25.0 g, 346 mmol), water (50 mL) and KSCN (67.2 g, 692 mmol) were stirred at room temperature for 20 hours. The organic layer was separated and dried over Na ₂ SO ₄ . The solid was filtered off to give the title compound (24.6 g, 87%) as a clear oil. _{^{1 HNMR (300MHz, CDCl 3)}} δ2.41 (s, 2H), 1.62 (s, 6H).

8b. 2- [4- (2-Methyl-2-sulfanylpropyl) piperazinyl] ethane-1-ol The product of Example 8a (1.0 g, 11.3 mmol) and 1- (2-hydroxyethyl) piperidine (2. 95 g, 22.7 mmol) was dissolved in benzene (1.5 mL) and heated at 80 ° C. for 2 hours. The mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was dried over Na ₂ SO ₄ . Volatiles were evaporated to give the title compound (2.06 g, 83%) as a white solid. ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.61 (t, J = 5.4, 2H), 2.66 to 2.71 (m, 4H), 2.52 to 2.56 (m, 6H), 2 .47 (s, 2H), 1.31 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 71.0, 59.2, 57.6, 55.5, 53.2, 46.4, 30 .1

8c. The product of Example 8b (5.9 g, 27.1 mmol) in 2- {4- [2-methyl-2- (nitrosothio) propyl] piperazinyl} ethane-1-ol CH ₂ Cl ₂ (100 mL) was added to 1N It was treated with _{HCl-Et 2 O (70mL)} . The solvent was removed to give a white solid. The solid was dissolved in EtOH (30 mL) and water (20 mL) and added dropwise to a stirring solution of t-BuONO (6.2 g, 54.1 mmol) in EtOH (10 mL). The reaction was kept at room temperature for 1 hour, after which volatiles were evaporated. The residue was partitioned between saturated NaHCO ₃ and EtOAc. The aqueous layer was extracted with EtOAc. The organic extracts were collected and dried over Na ₂ SO ₄ . Volatile material was evaporated. The residue was chromatographed on silica gel eluting with MeOH: CH ₂ Cl ₂ = 1: 19 to give the title compound (3.15 g, 47%) as a green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.67 (t, J = 5.3, 2H), 3.00 (s, 2H), 2.62 to 2.67 (m, 4H), 2.48 to 2 .54 (m, 6H), 1.88 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 68.1, 59.1, 58.8, 57.6, 55.4, 53.0, 27 .0; mass spectrum (m / e): 248 ( MH +).

8d. 2- {4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate The product of Example 8c (1. 52 g, 6.15 mmol) and 2-((2,6-dichlorophenyl) amino) benzeneacetic acid (2.19 g, 7.4 mmol) in CH ₂ Cl ₂ (20 mL) were added 1M in CH ₂ Cl _2. DCC (7.4 mL, 7.4 mmol) was added dropwise over 30 minutes. The reaction was kept at room temperature for an additional hour. Filter to remove the precipitate. The solvent was evaporated and the residue was chromatographed on silica gel eluting with Hex: EtOAc = 3: 1 to give the title compound (3.07 g, 95%) as a green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.34 (d, J = 8.0, 2H), 7.21 to 7.26 (m, 2H), 7.10 to 7.12 (m, 1H), 6 .94 to 7.01 (m, 2H), 6.87 (brs, 1H), 6.54 (d, J = 8.0, 1H), 4.26 (t, J = 5.8, 2H) 3.82 (s, 2H), 2.94 (s, 2H), 2.56 to 2.65 (m, 6H), 2.40 to 2.43 (m, 4H), 1.86 (s) , 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.27, 142.7, 137.7, 130.9, 129.5, 128.9, 127.9, 124.2, 124.0, 121. 9, 118.2, 68.1, 62.7, 38.8, 56.4, 55.2, 53.5, 38.6, 27.0; mass spectrum m / e): 525.

8e. 2- {4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate citrate Implementation in CH ₂ Cl ₂ (10 mL) The product of Example 8d (1.78 g, 3.39 mmol) was mixed with citric acid (0.65 g, 3.38 mmol) in MeOH (5 mL). The solvent was evaporated and the residue was dissolved in MeOH (10 mL) and EtOAc (10 mL). The mixture was cooled to -20 ° C to promote crystallization. The title compound (2.0 g, 82%) was collected by a funnel and dried in vacuo. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.42 (d, J = 8.1, 2H), 7.23 (dd, J = 7.5 and 1.2, 1H), 7.03 to 7.14 ( m, 2H), 6.90 (dd, J = 7.5 and 1.0, 1H), 6.37 (d, J = 8.0, 1H), 4.44 to 4.47 (t, J = 4.8, 2H), 3.87 (s, 2H), 3.29 to 3.31 (m, 1H), 3.22 (t, J = 4.8, 2H), 3.06 (s) , 2H), 2.86-2.95 (m, 4H), 2.70-2.81 (m, 8H), 1.86 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.4 166.0, 164.4, 135.8, 130.3, 123.7, 123.3, 121.6, 117.8, 116.3, 114.0, 109.6, 65. , 59.6,52.6,51.0,48.0,45.3,45.0,36.1,30.2,18.6.

Example 9: 2- [2- (tertiarybutyl) -5- (nitrosothio) -1,3-dioxan-5-yl] ethyl (2S) -2- [6-methoxy (2-naphthyl) propanoate 9a . 1,3-bis (1,1,2,2-tetramethyl-1-silapropoxy) acetone To a stirred solution of TBDMSCI (25.0 g, 116 mmol) in anhydrous pyridine, dihydroxyacetone dimer (7.5 g, 41.46 mmol) was added. The resulting solution was stirred at room temperature for 12 hours. Ethyl acetate (100 mL) was added and the solution was washed with 10% HCl (3 x 50 mL) and water (200 mL). The organic layer was dried over Na ₂ SO ₄ and evaporated to give the title compound (25.0 g, 94%) as a viscous oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.45 (s, 4H), 0.94 (s, 18H), 0.11 (s, 12H).

9b. Ethyl (2E) -4- (1,1,2,2-tetramethyl-1-silapropoxy) -3-[(1,1,2,2-tetramethyl-1-silapropoxy) methyl] butane-2 -Enoate To a solution of triethylphosphonoacetate (7.04 g, 31.4 mmol) in THF (50 mL) stirred at -78 C under nitrogen was added n-BuLi (2.5 M in hexane, 15. 0 mL, 37.5 mmol) was added. The resulting brownish solution was stirred for 30 minutes and a solution of the product of Example 9a (10.0 g, 31.4 mmol) in THF (10 mL) was added. The cooling bath was removed and the mixture was stirred at room temperature for 12 hours. Water (250 mL) was added and the mixture was extracted with EtOAc (3 x 100 mL). The organic layer was dried over Na ₂ SO ₄ . The solvent was evaporated to give the title compound (11 g, 90%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 5.9 to 6.01 (multit, 1H), 4.88 (s, 2H), 4.45 (s, 2H), 4.16 (q, J = 7.1 Hz) , 2H), 1.29 (t, J = 7.1 Hz, 3H), 0.95 (s, 9H), 0.91 (s, 9H), 0.10 (s, 6H), 0.08 ( s, 6H).

9c. 4- (hydroxymethyl) -4- (phenylmethylthio) -3,4,5-trihydrofuran-2-one The product of Example 9b (5.1 g, 13.1 mmol) and benzyl in piperidine (50 mL). Mercaptan (1.53 mL, 13.1 mmol) was heated at 100 ° C. for 4 hours and then cooled to room temperature. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (3 x 50 mL). The organic layer was collected and dried over Na ₂ SO ₄ . The solvent was evaporated and the residue was chromatographed on silica gel eluting with EtOAc: hexane = 5: 95 to give the title compound (4.6 g, 68%) as a viscous liquid. A viscous liquid (10.0 g, 19.5 mmol) was dissolved in CH ₃ CN (10 mL) and 48% HF (10 mL) was added. The solution was stirred at room temperature for 2 hours. Saturated NaHCO ₃ was added. The solution was extracted with EtOAc (3 x 100 mL). The organic layer was collected and dried over Na ₂ SO ₄ . The solvent was evaporated and the residue was chromatographed on silica gel eluting with EtOAc: hexane = 2: 1 to give the title compound (4.7 g, 95%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.22 to 7.30 (multit, 5H), 3.75 (s, 2H), (ABq, J = 9.9 Hz, 2H), 3.60 (d, J = 4.8 Hz, 2H), 2.04 to 2.08 (multit, 1H), (ABq, J = 17.8 Hz, 2H).

9d. 2- (Hydroxymethyl) -2- (phenylmethylthio) butane-1,4-diol To a solution of the product of Example 9c (3.8 g, 14.94 mmol) in THF (50 mL) stirred at 0 ° C. A solution of lithium aluminum hydride (1M in THF, 14.9 mL, 14.9 mmol) was added. The cooling bath was removed and the mixture was stirred at room temperature for 1 hour. Solid Na ₂ SO ₄ .10H ₂ O (3 g) was added in portions with stirring until a cloudy precipitate was formed. 10% MeOH in CH ₂ Cl ₂ (50 mL) was added and the solid separated by filtration. The solid was further washed with 10% MeOH in CH ₂ Cl ₂ (50 mL) and the solvent was evaporated. The residue was chromatographed on silica gel eluting with EtOAc: hexane = 4: 1 to give the title compound (2.4 g, 67%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.20-7.45 (multit, 5H), 4.00 (brs, 3H), 3.78 (t, J = 5.5 Hz, 2H), 3.67 (s , 2H), 3.46 (s, 4H), 1.84 (t, J = 5.5 Hz, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ) 137.7, 128.9, 128.7, 127. 3, 65.2, 58.2, 55.4, 35.7, 31.6.

9e. 2- [2- (tertiarybutyl) -5- (phenylmethylthio) -1,3-dioxan-5-yl] ethane-1-ol The product of Example 9d under stirring (1.02 g, 4. 2 mmol) and trimethylacetaldehyde (1.44 g, 16.8 mmol) in CH ₂ Cl ₂ (30 mL) was added BF ₃ .OEt ₂ (6 drops). The clear solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was chromatographed on silica gel eluting with EtOAc: hexane = 2: 1 to give the title compound (0.84 g, 64%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.04 to 7.21 (multit, 5H), 3.98 (d, J = 12.3 Hz, 2H), 3.91 (s, 1H), 3.85 (s , 2H), 3.60 (t, J = 6.3 Hz, 2H), 3.51 (d, J = 12.3 Hz, 2H), 1.38 (t, J = 6.3 Hz, 2H), 0 .78 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 138.0, 129.1, 128.5, 127.0, 108.2, 75.6, 58.3, 46.3, 37. 4, 34.9, 33.8, 24.7.

9f. 2- [2- (tertiarybutyl) -5-sulfanyl-1,3-dioxan-5-yl] ethane-1-ol The product of Example 9e (0.8 g, 2.6 mmol) was dissolved in THF (10 mL). ), Cooled to −78 ° C., and liquid NH ₃ (˜25 mL) was added. Sodium pieces (1.3 g) were added until the blue color continued for 10 minutes. Solid NH ₄ Cl (˜1 g) was added, the color disappeared, the cooling bath was removed and NH ₃ was evaporated (12 h). Water (100 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (0.51 g, 90%) as a white solid. Melting point 68 ° C. ¹ HNMR (300 MHz, CDCl ₃ ) δ 4.03 to 4.08 (multit, 13H), 3.88 (t, J = 6.1 Hz, 2H), 3.56 (d, J = 11.4 Hz, 2H) 2.15 (t, J = 6.1 Hz, 2H), 1.39 (s, 1H), 0.84 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 76.9, 59.4, 42.2, 39.2, 34.7, 24.5 (3C); mass spectrum (API-TIS) m / z 238 (M + NH ₄ )

9g. 2- [2- (tertiarybutyl) -5-sulfanyl-1,3-dioxane-5-yl] ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate at room temperature for 18 hours, (2S) -2- (6-Methoxy (2-naphthyl)) propanoyl chloride (0.56 g, 2.27 mmol) and the product of Example 9f (0.5 g, 2.27 mmol) in CH ₂ Cl ₂ (10 mL) The solution was stirred. The solvent was evaporated and the residue was chromatographed on silica gel eluting with EtOAc: hexane = 1: 9 to give the title compound (0.82 g, 83%) as a white solid. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.52 (d, J = 8.5 Hz, 3H), 7.26 (d, J = 8.4 Hz, 1H), 6.94 to 6.99 (multit, 2H) 4.09 to 4.19 (multit, 2H), 3.85 (s, 1H), 3.65 to 3.75 (multit, 3H), 3.71 (s, 3H), 3.27 (d , J = 4.1 Hz, 1H), 3.23 (d, J = 4.2 Hz, 1H), 2.01 to 2.09 (multit, 2H), 1.43 (d, J = 7.1 Hz, 3H), 0.99 (s, 1H), 0.74 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.3, 157.6, 135.5, 133.7, 129.2, 128 .9, 127.1, 126.3, 126.0, 118.9, 107.7, 105.6, 76.4 76.3,61.5,55.2,45.5,42.1,34.7,33.4,24.5, (3C), 18.3.

9h. 2- [2- (tertiarybutyl) -5- (nitrosothio) -1,3-dioxane-5-yl] ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate To a solution of Example 9g product (0.5 g, 1.15 mmol) in CH ₂ Cl ₂ (10 mL) was added t-BuONO (0.183 g, 1.38 mmol) and the resulting green solution was brought to room temperature. And stirred for 1 hour. The reaction mixture was washed with water (10 mL), dried over Na ₂ SO ₄ and concentrated to give the title compound (0.51 g, 96%) as a green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.64-7.72 (multit, 3H), 7.26-7.39 (multit, 1H), 7.11-7.16 (multit, 2H), 3.79 ˜4.49 (multit, 7H), 3.99 (s, 1H), 3.92 (s, 3H), 2.84 to 2.86 (multit, 2H), 1.58 (d, J = 7) .2 Hz, 3H), 0.99 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.3, 157.6, 135.4, 133.7, 129.2, 128.8, 127.2 , 126.2, 125.9, 118.9, 107.7, 105.6, 76.4, 76.3, 61.5, 55.2, 53.9, 45.4, 34.9, 32 4, 24.5, (3C), 18.2.

Example 10: 5- (Bis {[(nitrosothio) cyclohexyl] methyl} amino) pentyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate 10a. 5- (16-Aza-7,8-dithiadispiro [5.2.5.3] heptadecan-16-yl) pentan-1-ol The stirred product of Example 2a (5 g, 17.45 mmol) in CH ₂ Cl ₂ (75mL) solution was added 5-amino-1-pentanol (1.9 g, 18.32 mmol). The mixture was heated to reflux for 12 hours and then cooled to room temperature. Sodium triacetoxyborohydride (7.4 g, 34.9 mmol) was added and the resulting suspension was stirred at room temperature for 24 hours. The solution was added to water (200 mL). The organic layer was separated and dried over Na ₂ SO ₄ . The solvent was evaporated and the residue was chromatographed on silica gel eluting with EtOAc: hexane = 1: 1 to give the title compound (2.8 g, 45%). TLC R _f (0.45, EtOAc: hexane, 1: 2); ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.66 (t, J = 6.5 Hz, 2H), 2.84 (d, J = 14 Hz, 2H), 2.56 (d, J = 14 Hz, 2H), 2.35 to 2.70 (multit, 2H), 1.97 to 2.10 (multit, 2H), 1.10 to 1.80 ( ^13C NMR (75 MHz, CDCl ₃ ) δ 70.2, 62.6, 60.7, 55.5, 34.7, 33.6, 32.6, 28.1, 26.1, 23 3, 22.2, 21.8, 20.9; mass spectrum (API-TIS) m / z 358 (M + H).

10b. 5- (16-Aza-7,8-dithiadispiro [5.2.5.3] heptadecan-16-yl) pentyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate The product of Example 10a (2.6 g, 7.3 mmol), (2S) -2- (6-methoxy (2-naphthyl)) propanoic acid (2.0 g, 8.7 mmol) and DMAP (0.106 g, 0.87 mmol) of CH ₂ Cl ₂ (50 mL) was added dropwise with DCC (1.8 g, 8.72 mmol) in CH ₂ Cl ₂ (50 mL) at room temperature over 30 min. The resulting suspension was stirred at room temperature for 2 hours. The precipitate was separated by filtration and washed with CH ₂ Cl ₂ (25 mL). The filtrate was concentrated and the residue was chromatographed on silica gel eluting with EtOAc: hexane = 1: 9 to give the title compound (3.6 g, 86.7%) as a viscous oil. TLC R _f (0.43, EtOAc: hexane, 1: 9); ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.66-7.80 (multit, 3H), 7.39 (d, J = 8.4 Hz, 1H), 7.05 to 7.14 (multit, 2H), 4.06 (t, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.80 to 3.90 (multit, 1H), 2.75 (d, J = 13.8 Hz, 2H), 2.25 to 2.60 (multit, 4H), 1.56 (d, J = 7.0 Hz, 3H), 1.05 2.10 (multit, 26H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.0, 157.5, 135.7, 133.6, 129.2, 128.8, 127.0, 126.2, 125 .8, 118.9, 105.5, 70.3, 64.7, 60. , 55.5, 55.2, 45.4, 34.8, 33.7, 28.5, 28.0, 26.2, 23.5, 22.3, 21.9, 18.5; mass Spectrum (API-TIS) m / z 570 (M + H).

10c. 5- {Bis [(sulfanylcyclohexyl) methyl] amino} pentyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate Example in HOAc (50 mL) under nitrogen at room temperature for 24 hours A mixture of 10b product (3.25 g, 5.70 mmol) and zinc powder (5 g) was stirred. The inorganic solid was separated by filtration and washed with HOAc (25 mL). The filtrate was poured onto crushed ice and the mixture was basified with concentrated NH ₄ OH (15 mL). The white precipitate was extracted with EtOAc (2 x 50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was chromatographed on silica gel eluting with EtOAc: hexane = 1: 6 then 1: 1 to give the title compound (2.2 g, 68%) as a white foam. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.65 to 7.75 (multit, 3H), 7.39 (d, J = 8.4 Hz, 1H), 7.05 to 7.14 (multit, 2H), 4 .08 (t, J = 6.2 Hz, 2H), 3.89 (s, 3H), 3.80 to 3.89 (multit, 1H), 2.70 to 3.00 (multit, 4H), 2 .52 (d, J = 13.2 Hz, 2H), 1.56 (d, J = 7.2 Hz, 3H), 1.05 to 2.05 (multit, 26H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.5, 157.5, 135.6, 133.5, 129.1, 128.7, 127.0, 126.1, 125.8, 118.8, 105.4, 71.9, 70. 8, 64.4, 60.3, 56.6, 55.2, 53.1, 42.3, 4 .3, 40.8, 40.7, 28.2, 26.0, 25.6, 23.8, 23.6, 22.8, 22.5, 18.4; mass spectrum (API-TIS) m / z 572 (M + H).

10d. 5- (Bis {[(nitrosothio) cyclohexyl] methyl} amino) pentyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate Example 10c stirred under nitrogen at −78 ° C. To a solution of the product (0.4 g, 0.66 mmol) in CH ₂ Cl ₂ (25 mL) was added t-BuONO (210 μL, 1.58 mmol). The cooling bath was removed and the mixture was stirred for 15 minutes. Saturated Na ₂ CO ₃ (1 mL) was added and the mixture was shaken. The organic layer was separated and washed with water (50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was chromatographed on silica gel, eluting with EtOAc: hexane = 1: 9, to give the title compound (0.273 g, 66%) as a viscous oil. TLC R _f (0.27, EtOAc: hexane, 1: 9); ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.64-7.75 (multit, 3H), 7.38 (d, J = 8.4 Hz, 1H), 7.05 to 7.13 (multit, 2H), 3.99 to 4.03 (multit, 2H), 3.86 (s, 3H), 3.75 to 3.80 (multit, 1H) 3.24 (s, 4H), 2.42 to 2.49 (multit, 6H), 2.00 (t, J = 7.2 Hz, 3H), 1.55 (d, J = 7.1 Hz, 3H), 0.97-1.80 (multit, 18H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.0, 157.5, 135.6, 133.5, 129.1, 128.8, 126. 9, 126.1, 125.8, 118.8, 105.4, 67. , 64.4, 64.2, 56.6, 55.1, 45.3, 35.4, 28.3, 25.4, 24.1, 23.3, 22.3, 18.4; mass Spectrum (API-TIS) m / z 570 (M-2NO).

Example 11: 2 ({3-[(2S) -2- (6-methyl (2-naphthyl)) propanoyloxy] propyl} {[(nitrosothio) cyclohexyl] methyl} amino) acetic acid 11a. 3 [({[({[(3-Hydroxypropyl) amino] methyl} cyclohexyl) disulfanyl] cyclohexyl} methyl) amino] propan-1-ol CHCl ₃ (150 mL) (20 g, 69 .8 mmol) and propanolamine (10.5 g, 140 mmol) were heated to 65 ° C. for 8 hours. The solvent was evaporated to give a viscous yellow liquid that was dissolved in MeOH (200 mL). NaBH ₄ (5.3 g, 140 mmol) was added in portions over 10 minutes and the resulting solution was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was partitioned between water (200 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The organic layer was collected, dried over Na ₂ SO ₄ and concentrated to give the title compound (27.5 g, 97%) as a colorless viscous oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.84 (t, J = 5.3 Hz, 4H), 2.91 (t, J = 5.5 Hz, 4H), 2.66 (s, 4H), 1.20 ˜1.80 (multit, 24H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 64.8, 57.1, 54.4, 50.6, 34.4, 30.4, 25.8, 22.2.

11b. Tertiary butyl 2-({[({[({[(tertiary butyl) oxycarbonyl] methyl} (3-hydroxypropyl) amino) methyl] cyclohexyl} disulfanyl) cyclohexyl] methyl} (3-hydroxypropyl ) amino) was dissolved product acetate example 11a in _CH 3 CN (100mL), t- butyl bromoacetate _{(20g, 15mL, K 2 CO} 3 102.5 mmol) and solid (10 g) was added sequentially . The resulting suspension was stirred at room temperature for 12 hours. The solid was filtered off and washed with CH ₃ CN (50 mL). The filtrate was concentrated and the residue was chromatographed on silica gel eluting with EtOAc: hexane = 1: 2 to give the title compound (15.2 g, 88%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.49 (t, J = 5.1 Hz, 2H), 3.38 (s, 2H), 2.82 to 2.85 (multit, 2H), 1.39 (s , 9H), 0.90 to 1.65 (multit, 10H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.4, 81.0, 71.4, 60.5, 60.1, 59.2, 52 .4, 39.6, 28.4 (3C), 28.1 (3C), 26.0, 22.2 (2C); mass spectrum (API-TIS) m / z 304 (M + H).

11c. 3-({[({[({3-[(2S) -2- (6-methyl (2-naphthyl)) propanoyloxy] propyl} {[(tertiary butyl) oxycarbonyl] methyl} amino) Methyl] cyclohexyl} disulfanyl) cyclohexyl] methyl} {[(tertiary butyl) oxycarbonyl] methyl} amino) propyl (2S) -2- (6-methyl (2-naphthyl)) propanoate stirred at 0 ° C. The product of Example 11b (3.4 g, 5.7 mmol), (2S) -2- (6-methoxy (2-naphthyl)) propanoic acid (2.53 g, 11.0 mmol) and DMAP (0. To a solution of ₂ g) in CH ₂ Cl ₂ (30 mL) was added dropwise DCC (2.72 g, 13.2 mmol) in CH ₂ Cl ₂ (20 mL). The resulting suspension was stirred at 0 ° C. for 1 hour. The precipitate was separated by filtration and washed with CH ₂ Cl ₂ (25 mL). Concentrate the filtrate to give a green oil which is chromatographed on silica gel eluting with EtOAc: hexane = 1: 4 to give the title compound (2.8 g, 46.5%) as a white foam. Obtained. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.60 (t, J = 8.1 Hz, 3H), 7.31 (d, J = 8.4 Hz, 1H), 7.03 to 7.06 (multit, 2H) 4.00 to 4.11 (multit, 2H), 3.82 (s, 3H), 3.73 (q, J = 7.1 Hz, 1H), 3.22 (s, 2H), 2.68 (S, 2H), 2.61 to 2.68 (multit, 2H), 1.48 (d, J = 7.2 Hz, 3H), 1.36 (s, 9H), 1.10 to 1.66 (Multit, 12H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.6, 171.2, 157.5, 135.7, 133.6, 129.2, 128.8, 127.0, 126.2, 125.8, 118.9, 105.5, 80.7, 65.3, 62.1, 56.8, 56 0,55.2,52.8,45.4,28.1,27.4,25.6,22.2; mass spectrum (API-TIS) m / z393 (M + H).

11d. 2-({3-[(2S) -2- (6-methyl (2-naphthyl)) propanoyloxy] propyl} {[({[({3-[(2S) -2- (6-methyl ( 2-naphthyl)) propanoyloxy] propyl} (carboxymethyl) amino) methyl] cyclohexyl} disulfanyl) cyclohexyl] methyl} amino) acetic acid The product of Example 11c (2.2 g, 2.32 mmol) was added to CH ₂ Cl Dissolve in ₂ (10 mL) and add TFA (10 mL). The resulting solution was stirred at room temperature for 12 hours, then poured onto crushed ice and the resulting mixture was basified with concentrated NH ₄ OH (10 mL). The mixture was extracted with EtOAc (3 x 50 mL). The organic extracts were collected, dried over Na ₂ SO ₄ and filtered. The solvent was evaporated and the residue was chromatographed on silica gel eluting with MeOH: CH ₂ Cl ₂ = 1: 19 to give the title compound (1.6 g, 73%) as a white foam. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.63-7.70 (multit, 3H), 7.36 (d, J = 8.0 Hz, 1H), 7.10-7.26 (multit, 2H), 4 .08 (brs, 2H), 3.89 (s, 3H), 3.80 to 3.82 (multit, 1H), 3.32 (brs, 2H), 2.67 (brs, 4H), 1. 54 (d, J = 6.8 Hz, 3H), 1.17 to 1.80 (multit, 12H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.5, 157.6, 135.6, 133.6, 129.2, 128.8, 127.2, 126.2, 125.9, 119.0, 105.5, 62.4, 55.2, 45.4, 33.0, 25.4, 22. 0, 18.4; mass spectrum (API-TIS) m / z 945 (M + ).

11e. 2 ({3-[(2S) -2- (6-methyl (2-naphthyl)) propanoyloxy] propyl} {[(nitrosothio) cyclohexyl] methyl} amino) acetic acid The product of Example 11d (1.60 g, 1.69 mmol) was dissolved in HOAc (10 mL) and zinc powder (3.2 g) was added. The resulting suspension was stirred at room temperature for 12 hours. The inorganic solid was separated by filtration and washed with HOAc (25 mL). The filtrate was basified with conc. NH ₄ OH on crushed ice and then extracted with EtOAc (4 × 25 mL). The organic extracts were collected, dried over Na ₂ SO ₄ and filtered. The solvent was evaporated to give a white foam (1.4 g). The white foam was subsequently dissolved in CH ₂ Cl ₂ (15 mL) and concentrated HCl (2 mL) was added. 90% t-BuONO (0.41 mL, 3.43 mmol) was added via syringe. The resulting pale green solution was stirred at room temperature for 15 minutes and then poured onto crushed ice (-10 g). 10% Na ₂ CO ₃ was added and the mixture was extracted with EtOAc (3 × 50 mL). The organic extracts were collected, dried over Na ₂ SO ₄ and concentrated. The residue was chromatographed on silica gel eluting with EtOAc: hexane = 2: 1 to give the title compound (0.37 g, 22%) as a green oil (substantial decomposition occurred during work). ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.67 (t, J = 10.7 Hz, 3H), 7.35 (dd, J = 1.7 and 8.5 Hz, 1H), 7.10 to 7.26 ( multit, 2H), 3.96 to 4.02 (multit, 2H), 3.90 (s, 3H), 3.82 (q, J = 7.1 Hz, 1H), 3.32 (s, 2H) 3.27 (s, 2H), 2.58 (t, J = 7.4 Hz, 2H), 2.33 to 2.58 (multit, 2H), 1.85 (t, J = 13.3 Hz, 2H), 1.55 (d, J = 7.1 Hz, 3H), 1.30 to 1.72 (multit, 12H); ¹³ CNMR (75 MHz, CDCl ₃ ) δ 175.1, 174.5, 157.5 135.5, 133.6, 129.1, 128.8, 127.1, 126.1, 125.8. 118.9, 105.5, 66.8, 63.9, 62.2, 56.5, 55.2, 53.3, 45.3, 34.1, 26.5, 25.3, 21. 9, 18.2; mass spectrum (API-TIS) m / z 503 (M + H).

Example 12: 3- (Methyl {[1-methyl-4- (nitrosothio) (4-piperidyl)] methyl} amino) propyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate 12a. Ethyl 4- (methoxymethylene) piperidinecarboxylate Sodium hexamethyldisilazane in a suspension of (methoxymethyl) triphenylphosphonium chloride (120 g, 0.35 mol) in THF (100 mL) at −78 ° C. under nitrogen. A 1M THF solution of (NaHMDS, 350 mL, 0.35 mol) was added slowly. The resulting brown solution was stirred at −78 ° C. for 20 minutes, then 1-carbethoxy-4-piperidone (50 g, 0.292 mol) in THF (50 mL) was added dropwise. The mixture was stirred at −78 ° C. for 5 minutes and at room temperature for 2 hours. Water (200 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc and the organic extract was dried over Na ₂ SO ₄ . The solvent was evaporated to give an orange solid that was suspended in Et ₂ O (200 mL). The solid was removed by filtration and the filtrate was concentrated to a yellow oil that was triturated with hexane (200 mL). The precipitated white solid was removed by filtration. The filtrate was concentrated in vacuo and this procedure was repeated twice more to give the title compound (52 g, 89%) as a pale yellow oil. TLC R _f = 0.72 (EtOAc: hexane, 1: 2); ¹ HNMR (300 MHz, CDCl ₃ ) δ 5.84 (s, 1H), 4.11 (q, J = 7 Hz, 2H), 3.54 (S, 3H), 3.37 to 3.42 (multit, 4H), 2.24 (t, J = 5.6 Hz, 2H), 1.99 (t, J = 5.6 Hz, 2H), 1 .24 (t, J = 7 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 155.6, 140.8, 113.4, 61.3, 59.5, 45.8, 44.6, 29. 6, 25.2, 14.8; mass spectrum (API-TIS) m / z 200 (M + H). Analysis Calculated for _{C 10 H 17 N 1 O 3} ; C, 60.28; H, 8.60; N, 7.03. Observed; C, 60.29; H, 8.63; N, 6.81.

12b. Ethyl 4-formylpiperidinecarboxylate The product of Example 12a (52 g, 0.26 mol) and 1N HCl (75 mL) in CH ₃ CN (300 mL) was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was extracted with EtOAc (3 x 150 mL). The extracts were collected, washed with brine (2 × 150 mL), dried over Na ₂ SO ₄ and concentrated to give the title compound that was used in the next step without further purification. ¹ HNMR (300 MHz, CDCl ₃ ) δ 9.66 (s, 1H), 4.13 (q, J = 7 Hz, 2H), 3.90-3.99 (multit, 2H), 2.98 (multit, 2H) ), 2.42 (multit, 1H), 1.87 to 1.93 (multit, 2H), 1.63-1.49 (multit, 2H), 1.25 (t, J = 7 Hz, 3H).

12c. Ethyl 4-{[1- (ethoxycarbonyl) -4-formyl (4-piperidyl)] disulfanyl} -4-formylpiperidinecarboxylate solution of the product of Example 12c stirred at 50 ° C. in CCl ₄ (120 mL) To this was added S ₂ Cl ₂ (13.43 mL, 0.168 mol) dropwise over 5 minutes. After a short time (10-15 minutes), release of HCl gas was observed. After outgassing ceased, the mixture was stirred at 55 ° C. for 1 hour and then cooled to room temperature. The solvent is evaporated to give a yellow oil which is chromatographed on silica gel eluting with EtOAc: hexane = 1: 2 to give a pale yellow oil which is dried as a viscous oil by vacuum drying. The title compound (76% based on 12a)) was obtained, which solidified on standing at room temperature. ¹ HNMR (CDCl ₃ ) δ 9.04, 1H), 4.11 (q, J = 7 Hz, 2H), 3.65 to 3.85 (multit, 2H), 3.14 to 3.20 (multit, 2H) ), 2.01 to 2.07 (multit, 2H), 1.71 to 1.80 (multit, 2H), 1.25 (t, J = 7 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ193 .2,155.3,61.8,59.6,40.8,29.5,14.7; mass spectrum (API-TIS) m / z450 (M + NH 4).

12d. 3- (Methyl {[1-methyl-4- (nitrosothio) (4-piperidyl)] methyl} amino) propan-1-ol The product of Example 12c (7.0 g, 16.) in anhydrous CHCl ₃ (50 mL). 18 mmol) and propanolamine (2.91 g, 38.8 mmol) were heated at 65 ° C. for 8 hours. The solvent was evaporated to give a viscous yellow liquid, which was dissolved in MeOH (30 mL). NaBH ₄ (1.5 g, 38.83 mmol) was added in portions over 10 minutes and the resulting solution was stirred at room temperature for 1 hour. Formaldehyde 38% (30 mL) was added and the resulting cloudy solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was partitioned with a mixture of water (100 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The organic layer was collected, dried over Na ₂ SO ₄ and evaporated to give a colorless viscous oil (9.2 g). To a stirred solution of lithium aluminum hydride (1M, 42 mL, 42 mmol) under nitrogen at room temperature was added a colorless oil (8.2 g) in THF (50 mL). The can clear solution was stirred for 3 hours at room temperature, excess lithium aluminum hydride was destroyed by the addition of solid _Na 2 _SO 4 _· H 2 O a (to 10 g) little by little. The precipitate was separated by filtration and washed with 10% MeOH in CH ₂ Cl ₂ (2 × 50 mL). The filtrate was collected, dried over Na ₂ SO ₄ and concentrated to give a viscous liquid (5.1 g). The viscous liquid was dissolved in MeOH (30 mL), cooled to 0 ° C. and concentrated HCl (3 mL) was added. T-BuONO (3.2 mL, 26.8 mmol) was then added via syringe and the resulting green solution was stirred at room temperature for 20 minutes. The solution was poured onto crushed ice (to 10 _g), basified with _{10% Na 2 CO 3 (10mL} ). The green aqueous solution was extracted with EtOAc (3 x 50 mL). The organics were collected, dried over Na ₂ SO ₄ and concentrated. The residue was chromatographed on silica gel eluting with MeOH: CH ₂ Cl ₂ , 1; 4 to give the title compound (1.2 g). ¹ HNMR (CDCl ₃ ) δ 3.70 (t, J = 5.5 Hz, 2H), 3.23 (s, 2H), 2.74 to 2.80 (multit, 2H), 2.69 (t, J = 6.1 Hz, 2H), 2.50 to 2.67 (multit, 2H), 2.34 (s, 3H), 2.31 (s, 3H), 2.25 to 2.45 (multit, 4H) ), 1.67 (p, J = 5.9 Hz, 2H); ¹³ C NMR (CDCl ₃ ) δ 69.9, 62.9, 59.8, 51.4, 46.0, 44.3, 34.1 29.0; mass spectrum (API-TIS) m / z 26 (M + H).

12e. 3- (Methyl {[1-methyl-4- (nitrosothio) (4-piperidyl)] methyl} amino) propyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate Stir at room temperature Example 12d product (1.2 g, 4.59 mmol), (2-((2,6-dichlorophenyl) amino) benzene) acetic acid (2.01 g, 6.88 mmol) and DMAP (0.075 g) to the _CH 2 _Cl 2 (25mL) solution _was added CH ₂ Cl ₂ (25mL) solution of DCC (1.70 g, 8.26 mmol) dropwise. The resulting suspension was stirred at room temperature for 2 hours. The precipitate was filtered off and washed with CH ₂ Cl ₂ (25 mL). The filtrate was concentrated to give a green oil which was chromatographed on silica gel eluting with EtOAc: hexane 1: 1 then MeOH: CH ₂ Cl ₂ 1: 9 to give a green solid (contaminated with dicyclohexylurea). ). The solid was triturated with hexane (50 mL) and filtered. The filtrate was concentrated to give the title compound (1.4 g, 57%) as a viscous green oil. ¹ H NMR (CDCl ₃ ) δ 7.35-7.40 (multit, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.24-7.29 (multit, 1H), 7.14 (T, J = 7.5 Hz, 1H), 6.90 to 7.05 (multit, 3H), 6.56 (d, J = 7.9 Hz, 1H), 4.17 (t, J = 6. 3Hz, 2H), 3.82 (s, 2H), 3.17 (s, 2H), 2.75 to 2.79 (multit, 2H), 2.31 to 2.60 (multit, 8H), 2 .30 (s, 6H), 1.74-1.82 (multit, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.3, 142.7, 137.8, 130.8, 129.4, 128 .8, 127.9, 124.3, 123.9, 121.9, 118.2, 68.9, 63.2 61.6,56.5,51.6,46.1,44.4,38.6,33.8,26.7; mass spectrum (API-TIS) m / z539 (M + H).

12f. 3- (Methyl {[1-methyl-4- (nitrosothio) (4-piperidyl)] methyl} amino) propyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate citrate Citric acid (0 .43 g, 3.94 mmol) was dissolved in MeOH (1 mL) at 40 ° C. and the product of Example 12e (1.1 g, 2.03 mmol) was dissolved in EtOAc (2 mL). The solution was mixed and left at −20 ° C. for 2 hours. The light brown precipitate was filtered off and dried in vacuo for 3 hours to give the title compound (1.3 g, 88%) as a brown solid. Melting point 118 ° C. ¹ HNMR (300 MHz, d ₈ -THF) δ 7.57 (d, J = 8.0 Hz, 2H), 7.35 to 7.40 (multit, 1H), 7.05 to 7.25 (multit, 3H) 6.61 (d, J = 7.9 Hz, 1H), 4.30 (t, J = 6.3 Hz, 2H), 3.96 (s, 2H), 3.36 (s, 2H), 3, _{.14~3.18 (mult, 2H), 2.93} (AB q, 15.4Hz, 4H), 2.64~2.85 (mult, 8H), 2.58 (s, 3H), 2. _{47 (s, 3H); C} 31 H 40 N 4 O 10 S 1 Cl 2 relates calcd; C, 50.89; H, 5.51 ; N, 7.66; S, 4.38; Cl, 9.69. Observed; C, 50.64; H, 5.62; N, 7.52; S, 4.28; Cl, 9.89.

Example 13: 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate citrate 13a. Ethyl 2- {1-methyl-4-piperidylidene} acetate In a solution of triethylphosphonoacetate (17.5 g, 78.0 mmol) in THF (30 ml) stirred under a nitrogen atmosphere, n-BuLi (1.6 M in hexane, 58.7 ml, 93.6 mmol) was added at -78 ° C. The resulting brown solution was stirred for 30 minutes and then a solution of 1-N-methylpiperidone (8.8 g, 78.0 mmol) in THF (20 ml) was added. The cold bath was removed and the mixture was stirred at room temperature for 2 hours. Water (250 ml) was added and the mixture was extracted 3 times with 100 ml EtOAc. The organic extracts were combined and dried over Na ₂ SO ₄ . The solvent was evaporated to give the title compound (13.2 g, 92%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 5.64, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.00 (t, J = 5.1 Hz, 10H), 2.32-2 .53 (multiplex, 5H), 2.29 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.4, 158.6, 114. 2, 59.5, 56.7, 56.1, 45.7, 36.7, 29.3, 14.2.

13b. Ethyl 2- {1-methyl-4- (phenylmethylthio) piperidyl} acetate A solution of the product of Example 13a (13.2 g, 72.01 mmol) and benzyl mercaptan (8.4 ml, 72.01 mmol) in piperidine (35 ml). Was heated at 100 ° C. for 12 hours and then cooled to room temperature. Water (50 ml) was added and the aqueous layer was extracted 3 times with 100 ml EtOAc. The combined organic extracts were dried over Na ₂ SO ₄ . The solvent was evaporated and the residue was purified by silica gel chromatography eluting with 1: 9 MeOH: CH ₂ Cl ₂ to give the title compound (11.7 g, 53%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.18-7.34, (multiplex, 5H), 4.17 (q, J = 7.1 Hz, 2H), 3.71 (s, 2H), 2.64 ( s, 2H), 2.46 to 2.54 (multiplex, 4H), 2.29 (s, 3H), 1.83 to 1.95 (multiplex, 4H), 1.29 (t, J = 7. 1Hz, 3H).

13c. 2- [1-Methyl-4- (phenylmethylthio) -4-piperidyl] ethane-1-ol DIBAL in hexane to a stirred THF (40 ml) solution of the product of Example 13b (11.7 g, 38.74 mmol) The solution (83 ml, 83 mmol) was added at −78 ° C. under a nitrogen atmosphere. The cold bath was removed and the mixture was stirred for 1.5 hours. Solid Na ₂ SO ₄ .10H ₂ O (3 g) was added in portions with stirring until a thick precipitate formed. 10% MeOH in CH ₂ Cl ₂ (100 ml) was added and the mixture was filtered. The solid was washed with another 10% MeOH in CH ₂ Cl ₂ (100 ml) and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with 1: 9 MeOH: CH ₂ Cl ₂ to give the title compound (5.2 g, 50.6%) as a solid. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.20-7.35, (multiplex, 5H), 3.86 (t, J = 6.4 Hz, 2H), 3.66 (s, 2H), 2.50 2.57 (multiplex, 4H), 2.29 (s, 3H), 1.88 (t, J = 6.5 Hz, 2H), 1.65 to 1.84 (multiplex, 4H).

13d. 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethane-1-ol The product of Example 13c (7.8 g, 29.38 mmol) was dissolved in THF (50 ml) and cooled to −78 ° C. Liquid NH ₃ (˜100 ml) was then added. A small piece of Na (2 g) was added until the blue color persisted for 10 minutes. Solid NH ₄ Cl (˜5 g) was added until the color disappeared, the cold bath was removed and NH ₃ was evaporated (12 hours). Ether (100 ml) was added to the light yellow solid and HCl in ether (10 ml) was added until the solution was acidic. The mixture was left in the freezer for 30 minutes. The resulting solid was filtered and washed with 50 ml of ether. The residue was triturated with MeOH (100 ml) and undissolved material was removed by filtration. The solvent was concentrated to 25 ml and concentrated hydrochloric acid (2 ml) was added. 90% tertiary BuONO (3.1 ml, 23.7 mmol) was added via syringe. The resulting olive green solution was stirred at room temperature for 20 minutes and then poured onto crushed ice (5 g). 10% Na ₂ CO ₃ (10 ml) was added and the mixture was extracted 3 times with 50 ml EtOAc. The combined organics were dried over Na ₂ SO ₄ and concentrated to give the title product (3.6 g, 60%) as a green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.88, J = 6.9 Hz, 2H), 2.25 to 2.95 (multiplex, 13H), 2.30 (s, 3H), ¹³ CNMR (75 MHz, CDCl ₃ ) 62.5, 57.8, 51.5, 46.1, 36.4.

13e. 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate DCC in CH ₂ Cl ₂ (25 ml) (1.33 g 6.4 mmol) of the product of Example 13d (1.1 g, 5.38 mmol), {2-[(2,6-dichlorophenyl) amino] benzene} acetic acid (1.6 g, 5.38 mmol) and CH _2. To a stirred solution of DMAP (0.1 g) in Cl ₂ (25 ml) was added dropwise at room temperature. The resulting suspension was stirred for 2 hours at room temperature. The precipitate was filtered and washed with CH ₂ Cl ₂ (25 ml). The filtrate was concentrated to give a green oil which was chromatographed on silica gel eluting with 1: 1 EtOAc: hexane, then 1: 9 MeOH: CH ₂ Cl ₂ to give a green solid (with dicyclohexylurea as an impurity). . The solid was triturated with hexane (50 ml) and filtered. The filtrate was concentrated to give the title compound (2.1 g, 81%) as a viscous green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.25, J = 8.0 Hz, 2H), 7.21 (dd, J = 1.3 and 7.4 Hz, 1H), 7.11 to 7.14 (multiplex, 1H), 6.94 to 7.00 (multiplex, 2H), 6.82 (s, 1H), 6.55 (d, J = 7.9 Hz, 1H), 4.37 (t, J = 6. 9 Hz, 2H), 3.79 (s, 2H), 2.31 (s, 3H), 2.20 to 2.80 (multiplex, 10H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ 142.6, 137. 6, 130.9, 129.5, 128.8, 128.0, 124.0, 123.9, 122.0, 118.2, 61.5, 57.4, 51.4, 46.1, 38.6, 36.6, mass spectrum (API-TIS) m / z 483 (M + H).

13f. 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate citrate Citric acid (0.832 g, 3.94 mmol) Dissolved in MeOH (3 ml) at 40 ° C. and the product of Example 13e (1.9 g, 3.94 mmol) was dissolved in EtOAc (6 ml). The solution was mixed and left at −20 ° C. for 2 hours. The light brown precipitate was filtered off and dried in vacuo for 6 hours to give the title compound (2.3 g, 88%) as a brown solid. Melting point 130 ° C. ¹ HNMR (300 MHz, d _s -THF) δ 7.57 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 7.4 Hz, 1H), 7.19-7.26 (multiple, 3H), 7.05 (t, J = 7.4 Hz, 1H), 6.60 (d, J = 7.9 Hz, 1H), 4.53 (t, J = 6.8 Hz, 2H), 3. 93 (s, 2H), 3.25 to 3.40 (multiplex, 2H), 2.75 to 3.00 (multiplex, 12H), 2.69 (s, 3H). _{C 22 H 25 N 3 O 10} S 1 Cl 2 Analysis :( calculation) C49.86, H4.93, N6.23, S4.75 , Cl10.51, ( in fact) C49.84, H4.98, N6. 05, S4.73, Cl10.13.

Example 14: 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethyl 2- [4- (2-methylpropyl) phenyl] propanoate citrate 14a. 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethyl 2- [4- (2-methylpropyl) phenyl] propanoate DCC (0.824 g, 3.98 mmol in CH ₂ Cl ₂ (25 ml) ) Was added dropwise at room temperature to a stirred solution of the product of Example 13d (0.74 g, 3.62 mol), ibuprofen (074 g, 3.6 mmol)) and DMAP (75 mg) in CH ₂ Cl ₂ (25 ml). The resulting suspension was stirred for 1 hour at room temperature. The precipitate was filtered off and washed with CH ₂ Cl ₂ (25 ml). The filtrate was concentrated to give a green oil which was treated with silica gel chromatograph eluting with 1: 9 MeOH: CH ₂ Cl ₂ to give the title compound as a green solid (containing dicyclohexylurea as an impurity). The solid was triturated with hexane (50 ml) and filtered. The filtrate was concentrated to give the title compound (0.92 g, 65%) as a viscous green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.06-7.26 (multiplex, 4H), 4.25 (t, J = 6.5 Hz, 2H), 3.62 (q, J = 7.1 Hz, 1H) 2.28 (s, 3H), 2.21 to 2.67 (multiplex, 12H), 1.65 to 1.80 (multiplex, 1H), 1.45 (d, J = 7.2 Hz, 3H) , 0.88 (d, J = 6.6 Hz, 6H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.6, 140.7, 137.6, 129.5, 127.3, 61.5, 57. 7, 51.6 (2C), 46.2, 45.3, 45.2, 36.7, 36.5, 30.3, 22.5, 18.5, mass spectrum (API-TIS) m / z393 (M + H).

14b. 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethyl 2- [4- (2-methylpropyl) phenyl] propanoate citrate Citric acid (0.44 g, 2.29 mmol) at 40 ° C. Dissolve in MeOH (3 ml) and dissolve the product of Example 14a (0.9 g, 2.29 mmol) in EtOAc (5 ml). The solution was mixed and left at −20 ° C. for 2 hours. The light brown precipitate was removed by filtration and dried in vacuo for 6 hours to give the title compound (0.76 g, 58%) as a brown solid. Melting point 110 ° C. _{^{1 HNMR (300MHz, d s -THF}} ) δ7.32, J = 8.1Hz, 2H), 7.23 (d, J = 8.0Hz, 2H), 4.39 (t, J = 6.5Hz, 1H), 3.76 to 3.87 (multiplex, 1H), 2.55 to 3.30 (multiplex, 16H), 2.62 (s, 3H), 1.89 to 2.10 (multiplex, 1H) 1.55 (d, J = 7.1 Hz, 3H), 1.04 (d, J = 6.5 Hz, 6H). _{C 27 H 40 N 2 O 10} S 1 analysis :( calculation) C55.47, H6.90, N4.79, S5.48 , ( in fact) C55.23, H7.01, N4.58, S5.37 .

Example 15: 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethyl (2S) 2- [6-methoxy (2-naphthyl)] propanoate citrate 15a. 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethyl (2S) 2- [6-methoxy (2-naphthyl)] propanoate DCC in CH ₂ Cl ₂ (20 ml) (0.56 g, 2 0.7 mmol) of the product of Example 13d (0.5 g, 2.45 mmol), (2S) -2- [6-methoxy (2-naphthyl)] propanoic acid (0.56 g, 2.45 mmol) and CH ₂ To a stirred solution of DMAP (0.05 g) in Cl ₂ (20 ml) was added dropwise at room temperature. The resulting suspension was stirred for 1 hour at room temperature. The precipitate was filtered off and washed with CH ₂ Cl ₂ (25 ml). The filtrate was concentrated to give a green oil, which was treated with a 1: 9 MeOH: CH ₂ Cl ₂ eluting silica gel chromatograph to give a green solid (containing dicyclohexylurea as an impurity). The solid was triturated with hexane (50 ml) and filtered. The filtrate was concentrated to give the title compound (0.7 g, 69%) as a viscous green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.56 to 7.65 (multiplex, 3H), 7.01 to 7.29 (multiplex, 3H), 4.18 (t, J = 6.5 Hz, 2H), 3 .83 (s, 3H), 3.72 (q, J = 7.0 Hz, 1H), 2.51 (t, J = 6.6 Hz, 2H), 2.13 (s, 3H), 2.00 ˜2.60 (multiplex, 8H), 1.45 (d, J = 7.2 Hz, 3H), 1.47 (d, J = 7.1 Hz, 3H), ¹³ CNMR (75 MHz, CDCl ₃ ) δ174. 4, 157.7, 135.4, 133.7, 129.2, 128.9, 127.2, 126.1, 126.0, 119.0, 105.6, 61.1, 57.6, 55.3, 51.4, 51.3, 46.0, 45.4, 40.8, 36.5, 36.4, 18.2, mass Spectrum (API-TIS) m / z415 (M + H).

15b. 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethyl (2S) 2- [6-methoxy (2-naphthyl)] propanoate citrate Citric acid (0.33 g, 1.73 mmol) Dissolved in MeOH (3 ml) at 40 ° C. and the product of Example 15a (0.68 g, 1.73 mmol) was dissolved in EtOAc (5 ml). The solution was mixed and left at −20 ° C. for 2 hours. The light brown precipitate was filtered off and dried in vacuo for 6 hours to give the title compound (0.72 g, 68%) as a brown solid. Melting point 118 ° C. ¹ HNMR (300 MHz, d _s -THF) δ 7.82 to 7.89 (multiplex, 3H), 7.50 to 7.54 (multiplex, 1H), 7.37 to 7.38 (multiplex, 1H), 7 .27 (dd, J = 2.3 and 8.9 Hz, 1H), 4.41 (t, J = 6.5 Hz, 2H), 4.04 (s, 3H), 3.99 (q, J = 7.0 Hz, 1H), 2.94 (ABq, J = 15.3 Hz, Δv = 27 Hz, 4H), 2.79 (t, J = 6.4 Hz, 2H), 2.58 (s, 3H), 2.55 to 3.20 (multiplex, 8H), 1.67 (d, J = 7.1 Hz, 3H). _{C 28 H 36 N 2 O 11} S 1 analysis :( calculation) C55.25, H5.96, N4.60, S5.27 , ( in fact) C55.13, H5.88, N4.72, S5.23 .

Example 16: 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethyl 2- [3- (phenylcarbonyl) phenyl] propanoate citrate 16a. 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethyl 2- [3- (phenylcarbonyl) phenyl] propanoate DCC (0.33 g, 1.60 mmol) in CH ₂ Cl ₂ (20 ml). DMAP in the product of Example 13d (0.3 g, 1.47 mmol), 2- [3- (phenylcarbonyl) phenyl] propanoic acid (0.37 g, 1.47 mmol) and CH ₂ Cl ₂ (20 ml) 0.05 g) at room temperature. The resulting suspension was stirred for 1 hour at room temperature. The precipitate was filtered off and washed with CH ₂ Cl ₂ (25 ml). The filtrate was concentrated to give a green oil, which was treated with a 3:97 MeOH: CH ₂ Cl ₂ eluting silica gel chromatograph to give a green solid (with dicyclohexylurea as an impurity). The solid was triturated with hexane (50 ml) and filtered. The filtrate was concentrated to give the title compound (0.41 g, 63%) as a viscous green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.35 to 7.73 (multiplex, 9H), 4.20 (t, J = 6.6 Hz, 2H), 3.65 (q, J = 7.1 Hz, 1H) 2.20 (s, 3H), 2.10 to 2.65 (multiplex, 10H), 1.44 (d, J = 7.2 Hz, 3H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ 196.3, 173.7, 140.6, 137.9, 137.4, 132.4, 131.4, 130.0, 129.1, 129.0, 128.5, 128.3, 61.2, 57. 5, 51.4 (2C), 46.1, 45.3, 40.9, 36.6, 36.5, 18.2, mass spectrum (API-TIS) m / z 441 (M + H).

16b. 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethyl 2- [3- (phenylcarbonyl) phenyl] propanoate citrate Citric acid (0.18 g, 0.93 mmol) at 40 ° C. in MeOH (3 ml) and the product of Example 16a (0.41 g, 0.93 mmol) was dissolved in EtOAc (5 ml). The solution was mixed and left at −20 ° C. for 12 hours. The light brown precipitate was filtered off and dried in vacuo for 12 hours to give the title compound (0.45 g, 76%) as a brown solid. Mp 98-104 ° C. ¹ HNMR (300 MHz, d _s -THF) δ 7.62-7.97 (multiplex, 9H), 4.40 (t, J = 6.6 Hz, 2H), 3.97 (q, J = 7.1 Hz, 1H), 2.64 (s, 3H), 2.60-3.30 (multiplex, 14H), 1.63 (d, J = 7.1 Hz, 3H). _{C 30 H 36 N 2 O 11} S 1 analysis :( calculation) C56.95, H5.74, N4.43, S5.07 , ( in fact) C56.77, H5.92, N4.25, S4.92 .

Example 17: 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethyl 2 {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} acetate cyto Rate 17a. 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethyl 2 {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} acetate DCC (1.0 g 4.84 mmol) of the product of Example 13d (0.9 g, 4.40 mmol), 2- [1-methyl-4- (nitrosothio) -4-piperidyl] 2 {1-[(4-chlorophenyl) at room temperature. )] Carbonyl] -5-methoxy-2-methylindol-3-yl} acetic acid (1.57 g, 4.40 mmol) and added to a stirred solution of DMAP (0.05 g) in CH ₂ Cl ₂ (20 ml). The resulting suspension was stirred for 1 hour at room temperature. The precipitate was filtered off and washed with CH ₂ Cl ₂ (25 ml). The filtrate was concentrated to give a green oil which was treated with a 5:95 MeOH: CH ₂ Cl ₂ eluting silica gel chromatograph to give a green solid (containing dicyclohexylurea as an impurity). The solid was triturated with hexane (50 ml) and filtered. The filtrate was concentrated to give the title compound (1.85 g, 77%) as a viscous green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.47-7.65 (multiplex, 4H), 6.84-6.91 (multiplex, 2H), 6.65 (dd, J = 2.5 and 9.0 Hz, 1H), 4.29 (t, J = 6.7 Hz, 2H), 3.81 (s, 3H), 3.61 (s, 2H), 2.35 (s, 3H), 2.27 (s) 3H), 2.10-2.70 (multiplex, 10H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.5, 168.2, 156.1, 139.2, 135.9, 133.9, 131 .1, 130.7, 129.1, 114.9, 112.2, 111.6, 101.3, 61.3, 57.5, 55.7, 51.4 (2C), 46.1, 36.6, 30.3, 13.3, mass spectrum (API-TIS) m / z 544 (M + H).

17b. 2- [1-Methyl-4- (nitrosothio) -4-piperidyl] ethyl 2 {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} acetate citrate Citric acid ( 0.49 g, 2.57 mmol) was dissolved in MeOH (10 ml) at 40 ° C. and the product of Example 17a (1.4 g, 2.57 mmol) was dissolved in EtOAc (5 ml). The solution was mixed and left at −20 ° C. for 12 hours. The pale brown precipitate was filtered off and dried in vacuo for 12 hours to give the title compound (1.8 g, 95%) as a brown solid. Melting point 123 ° C. ¹ HNMR (300 MHz, d _s -THF) δ 7.86 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 6.81 (dd, J = 2. 3 and 8.9 Hz, 1H), 4.45 (t, J = 6.7 Hz, 2H), 3.95 (s, 3H), 3.84 (s, 2H), 2.57 to 3.20 ( Multiplex, 14H), 2.49 (s, 3H). _{C 33 H 38 N 3 O 12} S 1 Cl Analysis :( calculation) C55.84, H5.20, N5.71, S4.35 , Cl4.82, ( in fact) C53.69, H5.38, N5.57 , S4.30, Cl 4.61.

Example 18: 2- {Methyl [2-methyl {[(nitrosothiol) cyclohexyl] methyl} amino] ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate bisnitrate 18a. 2,2,2-trifluoro-N- {2-[(2-hydroxyethyl) amino] ethyl} acetamide 2- (2-aminoethylamino) ethanol (10 g, 96.01 mmol) was added to the dry ether (30 ml) with a syringe. ) In ethyl trifluoroacetate (13.64 g, 96.01 mmol) was added at 0 ° C. A white precipitate formed when the resulting solution was stirred at room temperature for 2 hours. The precipitate was filtered off, washed with ether (100 ml) and dried in vacuo for 3 hours to give the title compound (13.6 g, 100%). ¹ HNMR (300 MHz, CDCl ₃ ) δ (t, J = 5.1 Hz, 2H), 3.45 (t, J = 5.6 Hz, 2H), 2.86 (t, J = 5.6 Hz, 2H) 2.78 (t, J = 4.9 Hz, 2H), 2.22 (br s, 2H), mass spectrum (API-TIS) m / z 201 (M + H).

18b. N- {2-[(t-butoxy) -N- (2-hydroxyethyl) carbonylamino] ethyl} 2,2,2-trifluoroacetamide of the product of Example 18a (13.6 g, 67.96 mmol) BOC anhydride (14.83 g, 67.96 mmol) was added into a stirred THF (100 ml) solution and the mixture was stirred at room temperature for 2 hours. Water (200 ml) and EtOAc (100 ml) were added. The organic layer was isolated, dried over Na ₂ SO ₄ and concentrated to give the title compound (20 g, 98%) as a viscous oil. _{^{1 HNMR (300MHz, CDCl 3)}} δ2.35~3.75 (br multiplexing, 8H), 1.45 (s, 9H), mass spectrum (API-TIS) m / z301 (M + H).

18c. N- (2-aminoethyl) (t-butoxy) -N- (2-hydroxyethyl) carboxamide The product of Example 18b (20 g, 66.6 mmol), solid K ₂ CO ₃ and water in MeOH (50 ml). (10 ml) of the mixture was heated at 60 ° C. for 18 hours. Evaporation of the solvent gave a viscous oil that was extracted 5 times with 50 ml of EtOAc. The organics were combined and washed with water (50 ml). The organic phase was dried over Na ₂ SO ₄ and the solvent was evaporated to give the title oil (10 g, 66%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.74 (multiplex, 2H), 3.30-3.50 (multiplex, 3H), 2.90-3.10 (multiplex, 3H), 1.46 (s, 9H ), Mass spectrum (API-TIS) m / z 205 (M + H).

18d. 2- {methyl [methyl {[(nitrosothio) cyclohexyl] methyl} amino] ethyl} amino] ethane 1-ol The product of Example 2a (5.84 g, 20.4 mmol) and the product of Example 18c (10 g, 49.01 mmol) in dry CHCl ₃ (50 ml) was heated at 65 ° C. for 16 h. The solvent was evaporated to give a viscous yellow liquid, which was dissolved in MeOH (50 ml). NaBH ₄ (1.8 g, 47.3 mmol) was added in portions over 10 minutes and the resulting solution was stirred at room temperature for 1 hour. 38% formaldehyde (20 ml) was added and the resulting cloudy solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was partitioned between water (100 ml) and EtOAc (50 ml). The organic layer was separated and the aqueous layer was extracted twice with 50 ml EtOAc. The organic layers were combined, dried over Na ₂ SO ₄ and concentrated to give a colorless viscous oil (16 g). This viscous oil in THF (50 ml) was added dropwise to a stirred solution of lithium aluminum anhydride (1M, 60 ml, 60 mmol) at room temperature under a nitrogen atmosphere. The resulting clear solution was stirred at room temperature for 4 hours. Excess lithium aluminum anhydride was destroyed by adding Na ₂ SO ₄ .10H ₂ O (10 g) in small portions. The precipitate was filtered off and washed twice with 50 ml of 10% MeOH in CH ₂ Cl ₂ . The filtrates were combined, dried over Na ₂ SO ₄ and concentrated to give a viscous liquid (10 g). This viscous liquid (10 g) was dissolved in MeOH (30 ml) and cooled to 0 ° C. Concentrated HCl (5 ml) was added. 90% tertiary BuONO (5.4 ml, 38.4 mmol) was added via syringe and the resulting green liquid was stirred at room temperature for 20 minutes. The solution was poured onto crushed ice (-10 g) and the resulting mixture was made alkaline with 10% Na ₂ CO ₃ (10 ml). The green aqueous solution was extracted 3 times with 50 ml of EtOAc. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography eluting with 1: 9 MeOH: EtOAc to give the title compound (4.3 g). ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.57 (t, J = 5.3 Hz, 2H), 3.19 (s, 2H), 3.05 (br s, 1H), 2.38 (s, 3H) 2.27 (s, 3H), 2.11 to 2.80 (multiplex, 8H), 1.40 to 1.85 (multiplex, 6H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ 69.3, 64. 4, 58.9, 58.5, 58.4, 55.3, 45.3, 42.2, 34.2, 25.2, 22.2.

18e. 2- {Methyl [2-methyl {[(nitrosothiol) cyclohexyl] methyl} amino] ethyl} 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate DCC in CH ₂ Cl ₂ (25 ml) (1.20 g, 5.80 mmol) of the product of Example 18d (1.3 g, 4.75 mmol), {2-[(2,6-dichlorophenyl) amino] benzene} acetic acid (1.4 g, 4.75 mmol). ) And a stirred solution of DMAP (0.2 g) in CH ₂ Cl ₂ (25 ml) at room temperature. The resulting suspension was stirred for 3 hours at room temperature. The precipitate was filtered off and washed with CH ₂ Cl ₂ (25 ml). Concentration of the filtrate gave a green oil which was treated with silica gel chromatography eluting with 1: 1 EtOAc: hexane to give the title compound (0.82 g, 30.6%) as a viscous green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.32 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.90-6.99 (multiplex, 3H), 6.54 (d, J = 8.0 Hz, 1H), 4.22 (t, J = 5.8 Hz, 2H), 3.82 ( s, 2H), 3.13 (s, 2H), 2.43 to 2.66 (multiplex, 4H), 2.33 (s, 3H), 2.24 (s, 3H), 2.0 to 2 .15 (multiplex, 2H), 1.25 to 1.70 (multiplex, 6H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.3, 142.7, 137.8, 130.8, 129.5, 128 .8, 127.9, 124.3, 123.9, 121.9, 118.2, 69.1, 64.5, 63.0, 58.2 56.0,55.9,45.4,42.9,38.6,34.2,25.6,22.3.

18f. 2- {Methyl [2-methyl {[(nitrosothiol) cyclohexyl] methyl} amino] ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate bis nitrate Concentrated in dry acetone (1 ml) Nitric acid (0.12 g, 1.9 mmol) was added into a stirred solution of the product of Example 18e (0.45 g, 0.792 mmol) in dry acetone (3 ml). The resulting solution was left at −20 ° C. for 12 hours. The light brown precipitate was filtered off and dried in vacuo for 3 hours to give the title compound (0.406 g, 74%) as a brown solid. Melting point 78 ° C. ¹ HNMR (300 MHz, d _s -THF) δ 7.56, J = 8.0, 2H), 7.49 (d, J = 7.4 Hz, 1H), 7.16-7.26 (multiplex, 3H) 7.02 (t, J = 7.4 Hz, 1H), 6.56 (d, J = 7.9 Hz, 1H), 4.67 (t, J = 4.6 Hz, 2H), 4.07 ( s, 2H), 3.45 to 3.75 (multiplex, 6H), 3.07 (s, 3H), 2.76 (s, 3H), 2.65 to 2.79 (multiplex, 2H), 2 .69-2.76 (multiplex, 2H), 1.60-2.00 (multiplex, 6H). _{C 27 H 38 N 6 O 9} S 1 Cl 2 Analysis :( calculation) C46.76, H5.52, N12.12, S4.62 , Cl10.22, ( in fact) C46.73, H5.57, N12. 02, S4.90, Cl10.52.

Example 19: 2- {Methyl [2-methyl {[(nitrosothiol) cyclohexyl] methyl} amino] ethyl 2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindole-3- Yl} acetate 19a. 2- {Methyl [2-methyl {[(nitrosothiol) cyclohexyl] methyl}] ethyl 2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} acetate Solid DCC (2.86g, 13.81mmol) of the product of example 18d (3.0g, 10.97mmol), indomethacin (4.12g, 11.52mmol) and _CH 2 _Cl 2 (30ml) in DMAP (0. To the stirred solution of 2 g) at room temperature. The resulting suspension was stirred for 2 hours at room temperature. The precipitate was filtered off and washed with CH ₂ Cl ₂ (25 ml). The filtrate was concentrated to a green oil and treated with silica gel chromatography eluting with 1: 1 EtOAc: hexane to give the title compound (3.80 g, 56%) as a viscous green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.65 (J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 2.4 Hz, 1H) 6.85 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 4.17 ( t, J = 9.7 Hz, 2H), 3.83 (multiplex, 3H), 3.68 (s, 2H), 3.14 (s, 2H), 2.28 to 2.70 (multiplex, 8H) 2.38 (s, 3H), 2.34 (s, 3H), 2.23 (s, 3H), 2.05 to 2.15 (multiplex, 2H), 1.45 to 1.85 (multiplex) ^{, 6H), 13 CNMR (75MHz} , CDCl 3) δ170.8,168.3,155.9,139.2,135.9,133.8,131.1, 30.7, 129.1, 114.9, 112.5, 111.5, 101.3, 69.1, 64.5, 62.8, 58.2, 56.0, 55.6, 45. 4, 43.0, 34.2, 30.2, 25.5, 22.2, 13.4, mass spectrum (API-TIS) m / z 630 (M + H).

Example 20: 2-([(Dimethylamino) ethyl] {[(nitrosothio) cyclohexyl] methyl} amino) ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate 20a. 2,2,2-Trifluoro-N-[(methylamino) ethyl] acetamide To a stirred solution of ethyl trifluoroacetate (28.7 g, 204.34 mmol) in dry ether (50 ml) was added N-methylethylenediamine (15 g, 202 .3 mmol) was added dropwise at 0 ° C. The resulting solution was stirred at room temperature for 2 hours. Hexane (75 ml) is added and the solution is left at −20 ° C. for 16 hours to form a white precipitate which is filtered off, washed with ether (100 ml) and dried in vacuo for 3 hours to give the title compound. (29.4 g, 85%) was obtained. ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.42 (t, J = 5.8 Hz, 2H), 2.80 (t = 5.9 Hz, 2H), 2.43 (s, 3H), mass spectrum (API− TIS) 171 (M + H).

20b. N-{[(t-Butoxy) -N-methylcarbonylamino] ethyl} -2,2,2-trifluoroacetamide A solution of the product of Example 20a (29.0 g, 170.45 mmol) in stirred THF (100 ml) BOC anhydride (37.2 g, 170.4 mmol) was added and the mixture was stirred at room temperature for 2 hours. Water (200 ml) and EtOAc (100 ml) were added. The organic layer was isolated and dried over Na ₂ SO ₄ . The solvent was evaporated to give the title compound (45 g, 98%) as a viscous oil. _{^{1 HNMR (300MHz, CDCl 3)}} δ3.48 (br s, 4H), 2.90 (s, 3H), 1.45 (s, 9H), mass spectrum (API-TIS) m / z271 (M + H).

20c. N- (2-Aminoethyl) (t-butoxy) -N- (methyl) carboxamide The product of Example 20b (45 g, 166.5 mmol), solid K ₂ CO ₃ (15 g) in MeOH (100 ml) and water (10 ml) of the mixture was heated at 60 ° C. for 18 hours. Evaporation of the solvent gave a viscous oil that was extracted three times with 100 ml of EtOAc. The organics were combined, washed with water (100 ml) and dried over Na ₂ SO ₄ . The solvent was evaporated to give the title oily compound (7.8 g, 27%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.30 (t, J = 6.2 Hz, 2H), 2.91 (s, 3H), 2.88 (t, J = 6.4 Hz, 2H), 1.49 (S, 9H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ 79.4, 40.2, 34.6, 28.4 (3C), mass spectrum (API-TIS) m / z 175 (M + H).

20d. t-butyl 2-({[({[({[(t-butyl) oxycarbonyl] methyl} {2-[(t-butoxy) -N-methylcarbonylamino] ethyl} amino) methyl] cyclohexyl} disulfanyl ) Cyclohexyl] methyl} {2-[(t-butoxy) -N-methylcarbonylamino] ethyl} amino) acetate The product of Example 2a (5.34 g, 18.5 mmol) and the product of Example 20c (7 A mixture of .80 g, 44.76 mmol) in dry CHCl ₃ (75 ml) was heated at 65 ° C. for 16 hours. The solvent was evaporated to give a viscous yellow liquid, which was dissolved in MeOH (50 ml). NaBH ₄ (3.4 g, 89.5 mmol) was added in portions over 10 minutes and the resulting solution was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was dissolved in water (100 ml). The mixture was extracted 3 times with 75 ml EtOAc. The organic layers were combined, dried over Na ₂ SO ₄ and concentrated to give a colorless viscous oil (16 g). A colorless viscous oil (10.2 g) was dissolved in CH ₃ CN (100 ml), and t-butyl bromoacetate (20 g, 102.5 mmol) and solid K ₂ CO ₃ (10 g) were sequentially added. The resulting suspension was stirred at room temperature for 12 hours. The solid was filtered off and washed with CH ₃ CN (50 ml). The filtrate was concentrated and the residue was purified by silica gel chromatography eluting with 1: 9 EtOAc: hexane to give the title compound (6.3 g, 41% based on cyclohexanecarboxaldehyde disulfide) and unidentified low Rf product (2.2 g). Got. ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.38 (br s, 4H), 3.26 (br s, 4H), 2.87 (s, 10H), 2.84 (s, 4H), 1.47 ( s, 18H), 1.45 (s, 18H), 1.17 to 1.80 (multiplex, 20H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ 171.3, 155.5, 80.8, 79.1 65.6, 57.1, 56.1, 54.4, 47.7, 34.7, 32.7, 28.4 (3C), 28.2 (3C), 25.6, 22.3. (2C), mass spectrum (API-TIS) m / z 831 (M + H).

20e. 2-([(Dimethylamino) methyl] {[(Nitrosothio) cyclohexyl] methyl} amino) ethane-1-ol A stirred solution of lithium aluminum anhydride (1M, 23 ml, 23 mmol) in THF (50 ml) Example 20d Product (6.30 g, 7.58 mmol) was added dropwise under a nitrogen atmosphere. The resulting clear solution was stirred at room temperature for 1 hour, then heated to 70 ° C. for 12 hours and again cooled to room temperature. Excess lithium aluminum anhydride was destroyed by adding Na ₂ SO ₄ .10H ₂ O (10 g) in small portions. The precipitate was filtered off and washed twice with 50 ml of 10% MeOH in CH ₂ Cl ₂ . The filtrates were combined, dried over Na ₂ SO ₄ and concentrated to give a viscous liquid (3.2 g). This viscous liquid (3 g) was dissolved in MeOH (25 ml) and cooled to 0 ° C. Concentrated HCl (5 ml) was added. 90% tertiary BuONO (2.2 ml) was added via syringe and the resulting green liquid was stirred at room temperature for 20 minutes. The solution was poured onto crushed ice (-10 g) and the resulting mixture was made alkaline with 10% Na ₂ CO ₃ (10 ml). The green aqueous solution was extracted 3 times with 50 ml EtOAc, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography eluting with 1: 9 MeOH: CH ₂ Cl ₂ to give the title compound (0.7 g) (significant decomposition occurred in the chromatograph). ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.55, J = 5.3 Hz, 2H), 3.35 (s, 2H), 2.70 to 2.82 (multiplex, 4H), 2.50 to 2.60 (Multiplex, 2H), 2.22 (s, 6H), 2.10 to 2.40 (multiplex, 4H), 1.30 to 1.72 (multiplex, 6H), mass spectrum (API-TIS) m / z290 (M + H).

20f. 2-([(Dimethylamino) methyl] {[(Nitrosothio) cyclohexyl] methyl} amino) ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate DCC in CH ₂ Cl ₂ (10 ml) (0.59 g, 2.87 mmol) was converted to the product of Example 20e (0.7 g, 2.41 mmol), (2-[(2,6-dichlorophenyl) amino] benzene) acetic acid (0.71 g, 2.41 mmol). ) And a stirred solution of DMAP (0.1 g) in CH ₂ Cl ₂ (10 ml) at room temperature. The resulting suspension was stirred for 6 hours at room temperature. The precipitate was filtered off and washed with CH ₂ Cl ₂ (25 ml). Concentration of the filtrate gave a green oil that was viscous by chromatography on silica gel eluting with 1: 1 EtOAc: hexane followed by 1: 9 MeOH: CH ₂ Cl ₂ to give the title compound (0.3 g, 22%) as a viscous solution. As a green oil. _{^{1 HNMR (300MHz, CDCl 3)}} δ7.32 (d, J = 8.0Hz, 2H), 7.21 (d, J = 1.1Hz, 1H), 7.18 (d, J = 1.1Hz, 1H), 7.08-7.14 (multiplex, 1H), 6.91-6.99 (multiplex, 3H), 6.53 (d, J = 7.9 Hz, 1H), 4.19 (t, J = 6.2 Hz, 2H), 3.79 (s, 2H), 3.28 (s, 2H), 2.89 (t, J = 6.2 Hz, 2H), 2.72 to 2.74 ( Multiplex, 2H), 2.31 to 2.47 (multiplex, 4H), 2.19 (s, 6H), 2.01 to 2.11 (multiplex, 2H), 1.45 to 1.68 (multiplex, ^{6H), 13 CNMR (75MHz,} CDCl 3) δ172.2,142.6,137.7,130.8,129.4,128.8,127.9, 24.1, 123.9, 121.9, 118.1, 67.3, 64.4, 62.9, 57.1, 54.5, 54.4, 45.7, 38.6, 34. 2, 25.5, 22.2, mass spectrum (API-TIS) m / z 567 (M + H).

Example 21: 2- [4-Methyl-4- (nitrosothio) piperidyl] ethyl (2S) -2- [6-methoxy (2-naphthyl)] propanoate 21a. 2- (4-Methyl-4-sulfanylpiperidyl) ethyl (2S) -2- [6-methoxy (2-naphthyl)] propanoate The product of Example 1d (340 mg, 1.37 mmol) and (2S) -2- To a mixture of [6-methoxy (2-naphthyl)] propanoic acid (394 mg, 1.71 mmol) in CH ₂ Cl ₂ (10 ml) was added DCC (353 mg, 1.71 mmol) in one portion. Within 5 minutes white crystals began to form. The reaction was stirred overnight. Ether was added to the mixture and the solid was filtered off. The solvent was evaporated. The residue was chromatographed on silica gel eluting with 1: 3 EtOAc: hexane to give the title compound (420 mg, 1.08 mmol, 79%) as a clear oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.65-7.77 (multiplex, 3H), 7.38-7.42 (multiplex, 1H), 7.10-7.15 (multiplex, 2H), 4.12 ˜4.26 (multiplex, 2H), 3.91 (s, 3H), 3.85 (q, J = 7.1 Hz, 1H), 2.57 (t, J = 5.8 Hz, 2H), 2 .44 to 2.51 (multiplex, 2H), 2.28 to 2.38 (multiplex, 2H), 1.52 to 1.63 (multiplex, 7H), 1.33 (s, 3H).

21b. 2- [4-Methyl-4- (nitrosothio) piperidyl] ethyl (2S) -2- [6-methoxy (2-naphthyl)] propanoate The product of Example 21a is dissolved in ether and HCl in ether is added dropwise. did. The resulting white solid was collected, washed thoroughly with ether and dried in vacuo to give the hydrochloride salt (400 mg, 0.94 mmol) as a white solid. A white solid (400 mg, 0.94 mmol) was dissolved in CH ₂ Cl ₂ (4 ml) and cooled to 0 ° C. Tertiary butyl nitrite (187 μl, 1.42 mmol) was added. After 30 minutes the solvent was evaporated to give a green solid that was partitioned between saturated K ₂ CO ₃ and EtOAc. It was dried over _Na 2 SO ₄ and the combined EtOAc extract. The solvent was evaporated and the residue was chromatographed on silica gel eluting with 1: 1 EtOAc: hexane to give the title compound as a green solid. Melting point 131 ° C. _{^{1 HNMR (300MHz, CDCl 3)}} δ7.38~7.41 ( multi, 1H), 7.09~7.15 (multiplex, 2H), 4.13~4.30 (multiplex, 2H), 3.91 (S, 3H), 3.85 (q, J = 7.2 Hz, 1H), 2.54 to 2.63 (multiplex, 4H), 2.19 to 2.27 (multiplex, 4H), 1.96 -2.04 (multiplex, 2H), 1.87 (s, 3H), 1.58 (d, J = 7.1 Hz, 3H).

Example 22: 2- (Methyl {[1-methyl-4- (nitrosothio) (4-piperidyl)] methyl} amino) ethyl (2S) -2- [6-methoxy (2-naphthyl)] propanoate hydrochloride 22a . A suspension of t-butyl 6-aza-1-oxaspiro [2,5] octane-6-carboxylate NaH (3.13 g, 0.13 mol) in DMSO was trimethylsulfoxonium iodide (28.7 g, 0. 13 mol) was added in several portions. The mixture was stirred for 30 minutes. Tertiary butyl-4-oxopiperidinecarboxylate (20.0 g, 0.10 mmol) was added in one portion and the mixture was heated at 60 ° C. for 1 hour. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted twice with EtOAc. The organic layers were combined, dried over Na ₂ SO ₄ and then concentrated to give the title compound as a white solid (20.2 g, 9.46 mmol, 94%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.67-3.75 (multiplex, 2H), 3.37-3.46 (multiplex, 2H), 2.68 (s, 2H), 1.74-1.83 (Multiplex, 2H), 1.46 (s, 9H), 1.39 to 1.45 (Multiplex, 2H).

22b. t-Butyl 6-aza-1-thiaspiro [2,5] octane-6-carboxylate THF with the product of Example 22a (20.1 g, 9.44 mmol) and KSCN (27.5 g, 0.28 mol) A mixture in (94 ml) and water (94 ml) was stirred overnight. The reaction mixture was extracted with EtOAc. The organic extracts were combined, dried over Na ₂ SO ₄ and concentrated. The residue was chromatographed on silica gel eluting with 1: 3 EtOAc: hexane to give the title compound (16.1 g, 70 mmol, 75%) as white crystals. ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.90 to 3.96 (multiplex, 2H), 3.08 to 3.21 (multiplex, 2H), 2.43 (s, 2H), 2.00 to 2.09 (Multiplex, 2H), 1.43 (s, 9H), 1.35 to 1.43 (Multiplex, 2H).

22c. t-Butyl 4-{[(2-hydroxyethyl) methylamino] methyl} -4-sulfanylpiperidinecarboxylate Formation of Example 22b in 2- (methylamino) ethanol (17.5 ml) refluxed in benzene (35 ml) Product (5.0 g, 21.83 mmol) was added dropwise over 2.5 hours. The mixture was refluxed for an additional 2 hours, then cooled to room temperature and poured into water. The mixture was extracted twice with EtOAc. The organic extracts were combined, dried over Na ₂ SO ₄ and concentrated. The residue was chromatographed on silica gel eluting with 1: 3 EtOAc: hexane to give the title compound (3.15 g, 10.36 mmol, 48%). _{^{1 HNMR (300MHz, CDCl 3)}} δ3.92~3.98 ( multiplex, 2H), 3.64 (t, J = 5.3Hz, 2H), 3.13~3.19 ( multiplex, 2H), 2 .72 (t, J = 5.3 Hz, 2H), 2.59 (s, 2H), 2.41 (s, 3H), 1.61-1.70 (multiplex, 4H), 1.47 (s 9H).

22d. 2- {Methyl [(1-methyl-4-sulfanyl (4-piperidyl)) methyl] amino} ethane-1-ol To a solution of the product of Example 22c (3.92 g, 12.89 mmol) in THF (38 ml) Lithium aluminum anhydride (1M, 19.3 ml, 19.3 mmol) in THF was added. The mixture was refluxed overnight. The reaction was cooled to room temperature. Methanol was added to cool the reaction until no bubbles were observed, and then water was added until no more bubbles were generated. The mixture was filtered through celite and washed with 5:95 MeOH: CH ₂ Cl ₂ . The filtrate was concentrated to give the title compound (2.5 g, 11.46 mmol, 88%), which was used without further purification.

22e. 2- {Methyl [(1-methyl-4-sulfanyl (4-piperidyl)) methyl] amino} ethyl (2S) -2- [6-methoxy (2-naphthyl)] propanoate The product of Example 22d and {2 -[(2,6-dichlorophenyl) amino] benzene} acetic acid (1.41 g, 4.76 mmol) in CH ₂ Cl ₂ (20 ml) to a mixture of DCC (1 g, 4.76 mmol) in CH ₂ Cl ₂ (4 0.7 mmol) solution was added at 0 ° C. The mixture was warmed to room temperature and filtered through celite. The filtrate was concentrated and the residue was chromatographed on silica gel eluting with 5:95 MeOH: CH ₂ Cl ₂ to give the title compound (754 mg, 1.52 mmol, 32%) as a white foam. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.33 (d, J = 8.0 Hz, 2H), 7.20 to 7.23 (multiplex, 1H), 7.09 to 7.14 (multiplex, 1H), 6 .93 to 6.99 (multiplex, 3H), 6.54 (d, J = 8.0 Hz, 1H), 4.26 (t, J = 5.8 Hz, 2H), 3.82 (s, 2H) 2.85 (t, J = 5.8 Hz, 2H), 2.60 to 2.69 (multiplex, 2H), 2.52 (s, 2H), 2.41 (s, 3H), 2.33 ~ 2.37 (multiplex, 2H), 2.28 (s, 3H), 1.71-1.80 (multiplex, 2H), 1.57-1.61 (multiplex, 2H).

22f. 2- (Methyl {[1-methyl-4- (nitrosothio) (4-piperidyl)] methyl} amino) ethyl (2S) -2- [6-methoxy (2-naphthyl)] propanoate hydrochloride Formation of Example 22e To a stirred CH ₂ Cl ₂ (10 ml) solution of the product (HCl salt, 683 mg, 1.2 mmol) was added t-BuONO (138 mg, 1.2 mmol) in CH ₂ Cl ₂ (2 ml) over 5 min. The reaction mixture was stirred for 10 minutes. The reaction mixture was washed with saturated Na ₂ CO ₃ , dried over Na ₂ SO ₄ and concentrated. Treatment with silica gel chromatograph eluting with 2:98 MeOH: EtOAc afforded the title compound (612 mg, 1.02 mmol, 85%) as a green oil. The hydrochloride salt of this compound was prepared using HCl / ether. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.36 (d, J = 8.1 Hz, 2H), 7.23 to 7.27 (multiplex, 1H), 7.10 to 7.15 (multiplex, 1H), 6 .91 to 7.05 (multiplex, 2H), 6.51 (d, J = 8.0 Hz, 1H), 4.55 to 4.72 (multiplex, 2H), 3.90 (s, 2H), 2 .36-3.75 (multiplex, 12H), 2.84 (s, 3H), 2.81 (s, 3H).

Example 23: 3-[-4-Methyl-4- (nitrosothio) piperidyl] propyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate 23a. Methyl 3- (4-oxopiperidyl) propanoate Acetone with 4-oxopiperidine hydrochloride monohydrate (10.0 g, 65.1 mmol) and methyl 3-bromopropionate (7.8 ml, 71.6 mmol) To the (100 ml) suspension was added K ₂ CO ₃ (9.9 g, 71.6 mmol) and Et ₃ N (9.1 ml, 65.3 mmol). The mixture was refluxed for 24 hours. The solid was filtered off and the solvent was evaporated. The residue was partitioned between EtOAc and _{H 2} O. The organic extracts were combined and dried over Na ₂ SO ₄ . The solvent was evaporated to give the title compound as an oil (15.0 g, 27.0 mmol, 42%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.70 (s, 3H), 2.75 to 2.85 (multiplex, 6H), 2.562 to 2.57 (multiplex, 2H), 2.42 to 2.46 (Multiple, 4H).

23b. Methyl 3- (6-aza-1-oxaspiro [2,5] oct-6-yl) propanoate To a suspension of NaH (2.11 g, 52.7 mmol) in DMSO (100 ml) trimethylsulfoxonium iodide (11 .58 g, 52.62 mmol) was added in small portions. The mixture was stirred for 30 minutes. A solution of the product of Example 23a (7.49 g, 4.05 mmol) in DMSO (20 ml) was added and the mixture was heated to 60 ° C. for 1 hour. The reaction mixture was cooled to room temperature, poured into water and extracted with EtOAc. The organic extract was dried over Na ₂ SO ₄ . The solvent was evaporated to give the title compound (7.3 g, 36.7 mmol, 90.6%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.69 (s, 3H), 2.76 (t, J = 5.3 Hz, 2H), 2.50 to 2.65 (multiplex, 7H), 1.80 to 1 .85 (multiplex, 2H), 1.50 to 1.56 (multiplex, 2H).

23c. Methyl 3- (6-aza-1-thiaspiro [2,5] oct-6-yl) propanoate A solution of the product of Example 23b (6.2 g, 31.1 mmol) in MeOH (90 ml) in thiourea (2. 85 g, 37.4 mmol) was added. The reaction mixture was heated to 45 ° C. for 3 hours. The solvent was evaporated and the residue was triturated with ether and filtered. The filtrate was concentrated, triturated again with hexane and filtered. The solvent was evaporated to give the title compound (5.06 g, 23.5 mmol, 76%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.69 (s, 3H), 2.71 to 2.80 (multiplex, 4H), 2.34 to 2.56 (multiplex, 4H), 2.34 (s, 2H ), 2.10-2.20 (multiplex, 2H), 1.52-1.60 (multiplex, 2H).

23d. 3- (4-Methyl-4-sulfanylpiperidyl) propan-1-ol Lithium aluminum anhydride in THF (1M, 29.4 ml, 29.4 mmol) was charged with the product of Example 23c (5.06 g, 23.5 mmol). ) Was added dropwise at 0 ° C. over 20 minutes. The reaction was maintained at 0 ° C. for 1 hour. Methanol (5 ml) was added carefully followed by water (4 ml) to destroy excess lithium aluminum anhydride. The resulting solid was filtered off and washed with 1: 9 MeOH: CH ₂ Cl ₂ . The filtrates were combined and concentrated to give the title compound (2.93 g, 15.5 mmol, 66%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.79 (t, J = 5.2 Hz, 2H), 2.71 to 2.78 (multiplex, 2H), 2.65 (t, J = 5.7 Hz, 2H) 2.40-2.46 (multiplex, 2H), 1.68-1.75 (multiplex, 6H), 1.62 (s, 1H), 1.44 (s, 3H).

23e. 3- [4-Methyl-4- (nitrosothio) piperidyl] propan-1-ol To a mixture of the product of Example 23d (1.21 g, 6.40 mmol) in CH ₂ Cl ₂ was added HCl in ether. The solvent was evaporated to give a solid that was dissolved in ethanol (10 ml) and H ₂ O (2 ml). This homogeneous solution was slowly added to a stirred ethanol (10 ml) solution of t-BuONO (0.94 ml, 8.0 mmol) over 10 minutes. The reaction mixture was stirred for 1 hour. The solvent was evaporated and the residue was dissolved in CH ₂ Cl ₂ and washed with saturated Na ₂ CO ₃ . The organic layer was dried over Na ₂ SO ₄ and concentrated to give the title compound (1.25 g, 5.73 mmol, 90%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.82 (t, J = 5.2 Hz, 2H), 2.88-2.93 (multiplex, 2H), 2.65 (t, J = 5.7 Hz, 2H) 2.47 to 2.53 (multiplex, 2H), 2.30 to 2.42 (multiplex, 2H), 2.21 to 2.28 (multiplex, 2H), 2.00 (s, 2H), 1 .70 to 1.76 (multiplex, 2H).

23f. 3- [4-Methyl-4- (nitrosothio) piperidyl] propyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate The product of Example 23e (0.68 g, 3.12 mmol) and { A suspension of 2-[(2,6-dichlorophenyl) amino] benzene} acetic acid (1.20 g, 4.05 mmol) in CH ₂ Cl ₂ (10 ml) was added to a DCC (1M solution in CH ₂ Cl ₂ ). 05 ml, 4.05 mmol) was added over 15 minutes. DMAP (1 mg) was added and allowed to react with stirring at room temperature for 1.5 hours. The formed solid was removed by filtration. The solvent was evaporated and the residue was purified by silica gel chromatography to give the title compound (770 mg, 1.55 mmol, 50%) as a green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.33 (d, J = 8.1 Hz, 2H), 7.21 to 7.26 (multiplex, 1H), 7.10 to 7.12 (multiplex, 1H), 6 91 to 7.00 (multiplex, 3H), 6.54 (d, J = 8.0 Hz, 1H), 4.22 (t, J = 6.5 Hz, 2H), 3.80 (s, 2H) 2.66-2.70 (multiplex, 2H), 2.18-2.48 (multiplex, 8H), 1.98 (s, 3H), 1.82-1.88 (multiplex, 2H), ¹³ CNMR (75 MHz, CDCl ₃ ) δ 172.3, 142.7, 137.8, 130.8, 129.5, 128.9, 127.9, 124.3, 124.0, 122.0, 118.2 63.7, 55.9, 54.8, 49.9, 38.7, 38.3, 36.2.

Example 24: 3- [4-Methyl-4- (nitrosothio) piperidyl] propyl (2S) -2- [6-methoxy (2-naphthyl)] propanoate 24a. 3- [4-Methyl-4- (nitrosothio) piperidyl] propyl (2S) -2- [6-methoxy (2-naphthyl)] propanoate (2S) -2- [6-methoxy (2-naphthyl)] propanoic acid DCC in CH ₂ Cl ₂ (3.9 ml) in a suspension of CH ₂ Cl ₂ (10 ml) with (901 mg, 3.91 mmol) and the product of Example 23e (0.57 g, 2.61 mmol) 800 mg, 3.9 mmol) was added over 15 minutes. DMAP (3 mg) was added and allowed to react with stirring at room temperature for 1.5 hours. The formed solid was removed by filtration. The solvent was evaporated and the residue was purified by silica gel chromatography to give the title compound as a green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.65-7.69 (multiplex, 3H), 7.37-7.41 (multiplex, 1H), 7.09-7.14 (multiplex, 2H), 4.08 ~ 4.15 (multiplex, 2H), 3.90 (s, 3H), 3.79 to 3.86 (multiplex, 1H), 2.52 to 2.56 (multiplex, 2H), 2.35-2 .39 (multiplex, 2H), 2.12 to 2.27 (multiplex, 6H), 1.93 (s, 3H), 1.70 to 1.77 (multiplex, 2H), 1.26 (d, J = 2.8 Hz, 3H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.6, 157.6, 135.7, 133.7, 129.2, 128.9, 127.1, 126.2, 125. 9, 119.0, 105.6, 63.0, 55.8, 55.3, 54.7, 49.8, 45.5, 3 .2,26.1,18.3.

Example 25: 2- [2-({N- [2-Methyl-2- (nitrosothio) propyl] carbamoyl} methoxy) acetylamino] ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} Acetate 25a. 2-{[N- (2-Methyl-2-sulfanylpropyl) carbamoyl] methoxy} acetic acid 1-amino-2-methyl-2-propanethiol hydrochloride (4.21 g, 29.7 mmol) in ice-cold CH ₂ Cl ₂ (50 ml) To the suspension was added Et ₃ N (4.56 ml, 32.7 mmol) followed by diglycolic anhydride (3.43 g, 29.6 mmol). After stirring at room temperature for 30 minutes, the reaction was concentrated in vacuo. To the residue was added cold 2N hydrochloric acid (50 ml). The mixture was extracted 5 times with 30 ml EtOAc. The extracted organics were combined, washed with brine (30 ml) and dried over Na ₂ SO ₄ . Concentration and trituration with ether: hexanes afforded the title compound (5.50 g, 84.2%) as a white solid. Melting point 81-82 ° C. ¹ HNMR (300 MHz, CDCl ₃ ) δ 8.80 (br s, 1H), 7.48 (br s, 1H), 4.24 (s, 2H), 4.20 (s, 2H), 3.41 ( d, J = 6.4 Hz, 2H), 1.59 (s, 1H), 1.38 (s, 6H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.8, 170.4, 70.8, 68 .4, 51.9, 44.9, 29.8, mass spectrum (API-TIS) m / z 239 (M + NH ₄ ), 222 (M + H).

25b. 2-({N- [2-Methyl-2- (nitrosothio) propyl] carbamoyl} methoxy) acetic acid A solution of the product of Example 25a (5.76 g, 26.03 mmol) in CH ₂ Cl ₂ (100 ml) at room temperature. t-BuONO (3.2 ml, 27.37 mmol) was added. After 30 minutes, the reaction was concentrated and the residue was cooled to solidify. Washing with EtOAc: hexane gave the title compound (6.41 g, 98%) as green crystals. Mp 81-83 ° C. ¹ HNMR (300 MHz, CDCl ₃ ) δ 8.49 (br s, 1H), 7.28 (br s, 1H), 4.18 (s, 2H), 4.17 (s, 2H), 4.12 ( d, J = 6.5 Hz, 2H), 1.90 (s, 6H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ 173.0, 170.7, 70.9, 68.4, 56.7, 49. 0,26.8, mass spectrum (API-TIS) m / z268 (M + NH 4), 251 (M + H). _{C 8 H 14 N 2 O 5} S Analysis :( calculation) C38.39, H5.64, N11.19, S12.18 , ( in fact) C38.56, H5.76, N10.88, S12.96 .

25c. 2-{[N- (hydroxyethyl) carbamoyl] methoxy} -N- [2-methyl-2- (nitrosothio) propyl] acetamide CH ₂ Cl ₂ of the product of Example 25b (1.0 g, 4.0 mmol) To the (50 ml) solution was added ethanolamine (0.27 g, 4.42 mmol) followed by hydroxysuccinamide (509 mg, 4.4 mmol). Next, DCC (824 mg, 4.0 mmol) in CH ₂ Cl ₂ (4 ml) was added, and the mixture was reacted at room temperature for 30 minutes. The reaction mixture was poured into water (50 ml) and extracted 6 times with EtOAC. The solvent was evaporated to give the title compound that was used in the next reaction without further purification.

25d. 2- [2-({N- [2-Methyl-2- (nitrosothio) propyl] carbamoyl} methoxy) acetylamino] ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate Example 25c Of DCC (1 g, ˜4.0 mmol) and {2-[(2,6-dichlorophenyl) amino] benzene} acetic acid (1.4 g, 4.8 mmol) in CH ₂ Cl ₂ (50 ml). 4.8 mmol) of CH ₂ Cl ₂ (4.8 ml) was added followed by DMAP (25 mg). The mixture was stirred at room temperature for 4 hours. The solid was filtered off. The filtrate was concentrated and the residue was treated with EtOAc extracted silica gel chromatograph to give the title compound (1.08 g, 1.89 mmol, 47% over 2 steps) as a green foam. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.34 (d, J = 8.1 Hz, 2H), 7.20 (dd, J = 1.0 and 7.5 Hz, 1H), 7.13 (t, J = 7.7 Hz, 2H), 6.92 to 7.02 (multiplex, 2H), 6.54 (d, J = 7.0 Hz, 1H), 4.29 (t, J = 5.1 Hz, 2H), 4.0 (d, J = 7.5 Hz, 2H), 3.98 (s, 2H), 3.92 (s, 2H), 3.82 (s, 2H), 3.57 to 3.63 ( Multiple, 2H), 1.87 (s, 6H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.7, 168.8, 168.4, 142.5, 137.5, 130.8, 129.4, 128.9, 128.1, 124.2, 123.8, 122.0, 118.2, 70.7, 63.7, 57.1, 9.1,38.6,38.3,26.7.

Example 26: [2-({N- [2-Methyl-2- (nitrosothio) propyl] carbamoyl} methoxy) acetyloxy] methyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate 26a . Chloromethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate {2-[(2,6-dichlorophenyl) amino] benzene} sodium acetate (10 g, 31 mmol), NaHCO ₃ (9.9 g, 44 mmol), CH ₂ Cl ₂ (90 ml) in n-Bu ₄ NOH (1 ml, 40 wt% in H ₂ O) and H ₂ O (90 ml) in a slurry of chloromethyl chlorosulfate (4.5 ml, 44 mmol) in CH ₂ A Cl ₂ (10 ml) solution was added over 15 minutes. After stirring for 1 hour, the two-phase slurry became clear. The layers were separated and the aqueous phase was extracted with CH ₂ Cl ₂ . The organic layers were combined, washed with 5% NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated. The residue was recrystallized from 5: 1 hexane: EtOAC (25 ml) to give the title compound (12 g, 89%). Mp 89-91 ° C. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.35 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.8 Hz, 1H), 7.15 (dt, J = 1.4 and 7.6 Hz, 1 H), 6.99 (t, J = 8.0 Hz, 1 H), 6.99 (d, J = 7.3 Hz, 1 H), 6.58 (d, J = 7.6 Hz, 1 H) ), 6.56 (s, 1H), 5.74 (s, 2H), 3.90 (s, 2H). C ₁₅ H ₁₂ Cl ₃ NO ₂ Analysis :( calculation) C52.28, H3.51, N4.06, Cl30.86 , ( in fact) C52.18, H3.64, N3.94, Cl30.67 .

26b. Indomethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate The product of Example 26a (710 mg, 2 mmol) and NaI (1.8 g, 12 mmol) were dissolved in acetone (6 ml) at room temperature. Stir overnight. A 1: 1 mixture of ether: hexane (30 ml) was added to precipitate the inorganic salt and the precipitate was filtered off. The filtrate was evaporated and the residue was recrystallized from 10: 1 EtOAc: hexane (2 ml) to give the title compound (450 mg, 50%). Melting point 66 ° C. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.34 (d, J = 8.0 Hz, 2H), 7.22 (dd, J = 1.4 and 7.8 Hz, 1H), 7.15 (dt, J = 1.5 and 7.6 Hz, 1H), 6.96 to 7.02 (multiplex, 2H), 6.57 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 5. 94 (s, 2H), 3.84 (s, 2H). C ₁₅ H ₁₂ Cl ₂ INO ₂ analysis: (calculated) C41.32, H2.77, N3.20, Cl16.26, I29.10 (actual) C41.59, H2.81, N3.20, Cl16.16 I28.99.

26c. [2-({N- [2-Methyl-2- (nitrosothio) propyl] carbamoyl} methoxy) acetyloxy] methyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate Formation of Example 25b Product (0.39 g, 1.56 mmol) and the product of Example 26b (0.57 g, 1.31 mmol) in CH ₂ Cl ₂ (10 ml) with i-Pr ₂ NEt (0.27 ml, 1.56 mmol). Was added. The reaction was allowed to stir at room temperature for 2 hours. The solvent was evaporated. The residue was chromatographed on silica gel eluting with 1: 4 EtOAc: hexane to give the title compound (233 mg, 0.42 mmol, 32%) as a green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.33 (d, J = 8.1 Hz, 2H), 7.22 (dd, J = 1.3 and 7.5 Hz, 1H), 7.12 to 7.15 ( Multiplex, 2H), 7.00 to 7.02 (multiplex, 2H), 6.56 (d, J = 8.1 Hz, 1H), 5.84 (s, 2H), 4.13 (s, 2H) 4.07 (d, J = 6.8 Hz, 2H), 4.06 (s, 2H), 3.87 (s, 2H), 1.89 (s, 6H), ¹³ C NMR (75 MHz, CDCl ₃ ) 170.7, 169.0, 168.4, 142.5, 137.5, 130.9, 129.3, 128.8, 128.3, 124.1, 123.3, 122.3, 118 .5, 79.6, 71.0, 68.0, 56.8, 48.8, 38.0, 31.5, 26.7, 2 .6,14.1,14.0.

Example 27: 2- [4- (Nitrosothio) -4-piperidyl] ethyl (2S) -2- [methoxy (2-naphthyl)] propanoate hydrochloride 27a. 2- {1-[(t-Butyl) oxycarbonyl] -4-sulfanyl-4-piperidyl} ethyl (2S) -2- [6-methoxy (2-naphthyl)] propanoate The product of Example 6d (210 mg, 0.8 mmol) and pyridine were dissolved in CH ₂ Cl ₂ (5 ml) and cooled to 0 ° C. A solution of (2S) -2- [6-methoxy (2-naphthyl)] propanoic acid hydrochloride (200 mg, 0.8 mmol) in CH ₂ Cl ₂ (2 ml) was added dropwise. Stirring was continued for 1 hour to return the reaction to room temperature. Additional chloride (150 g, 0.6 mmol) was added and stirring was continued for 1 hour. Diluted with the reaction solicitation was _{CH 2 Cl 2 (25ml),} 1N hydrochloric acid, saturated NaHCO _3, washed once with 15ml of brine and dried over _Na 2 SO _4. The solvent was evaporated and treated on a silica gel chromatograph eluting with 5: 1 hexane: EtOAc to give 210 g (55%) of the title compound. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.64-7.72 (multiplex, 3H), 7.37 (dd, J = 1.8 and 8.5 Hz, 1H), 7.11-7.16 (multiplex, 2H), 4.35 (d, J = 6.8 Hz, 2H), 3.91 (s, 3H), 3.82 (q, J = 7.1 Hz, 1H), 3.72 to 3.78 ( Multiplex, 2H), 3.13 (ddd, J = 6.7, 10.8 and 15 Hz, 2H), 1.87 (dt, J = 1.5 and 6.7 Hz, 2H), 1.57 (d , J = 7.1 Hz, 3H), 1.44 (s, 9H), 1.48 to 1.53 (multiplex, 2H).

27b. 2- [4-sulfanyl-4-piperidyl] ethyl (2S) -2- [6-methoxy (2-naphthyl)] propanoate hydrochloride The product of Example 27a (370 mg, 0.8 mmol) in ether (6 ml) Of 4.9 M HCl. The reaction was allowed to stir at room temperature for 2 hours. During this time a precipitate formed. The solid was filtered off, washed with fresh ether and dried in vacuo. This gave 230 mg (70%) of the title compound. Mp 222-225 ° C. ¹ HNMR (300 MHz, d ₆ -DMSO) δ 9.02 (br s, 1H), 8.88 (br s, 1H), 7.76-7.81 (multiplex, 2H), 7.70 (s, 1H ), 7.37 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 2.4 and 9.0 Hz, 1H) 4.26 (d, J = 6.4 Hz, 2H), 3.89 (q, J = 6.8 Hz, 1H), 3.85 (s, 3H), 2.93 to 3.03 (multiplex, 5H), 1.87 (d, J = 6.7 Hz, 2H), 1.55-1.81 (multiplex, 4H), 1.46 (d, J = 7.1 Hz, 3H). C ₂₁ H ₂₇ NO ₃ S · HCl analysis: (calculated) C61.52, H6.88, N342, Cl8.65, (actual) C61.50, H6.92, N3.38, Cl8.67.

27c. 2- [4- (Nitrosothio) -4-piperidyl] ethyl (2S) -2- [6-methoxy (2-naphthyl)] propanoate hydrochloride The product of Example 27b (50 mg, 0.12 mmol) was treated with acetic acid (2 ml ) And CH ₂ Cl ₂ (6 ml), cooled to 0 ° C. and shielded from light. Tertiary BuONO (22 ml, 0.18 mmol) was added and the mixture was stirred for 1 hour. CH ₂ Cl ₂ was removed on a rotary evaporator and acetic acid was removed by lyophilization. The title compound was thus obtained as a bright green powder. ¹ HNMR (300 MHz, d ₆ -DMSO) δ 11.91 (brs, 1H), 8.96 (brs, 1H), 7.75-7.80 (multiplex, 2H), 7.67 (s, 1H ), 7.33 (dd, J = 1.6 and 8.5 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 2.5 and 8.H). 9 Hz, 1 H), 4.21 (d, J = 6.2 Hz, 2 H), 3.86 (q, J = 7.0 Hz, 1 H), 3.85 (s, 3 H), 3.11 1-3. 30 (multiplex, 2H), 2.82 to 3.02 (multiplex, 2H), 2.35 to 2.60 (multiplex, 6H), 1.43 (d, J = 7.1 Hz, 3H).

Example 28: {[3- (Methyl {[(nitrosothio) cyclohexyl] methyl} amino) propyl] oxycarbonyl} methyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate 28a. {[3- (Methyl {[(nitrosothio) cyclohexyl] methyl} amino) propyl] oxycarbonyl} methyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate 2- (2- {2- [ (2,6-Dichlorophenyl) amino] phenyl} acetyloxy) acetic acid (115 mg, 0.32 mmol), the product of Example 4c (80 mg, 0.32 mmol) and DMAP (20 mg, 0.16 mmol) in CH ₂ Cl ₂ (4 ml). DCC (70 mg, 0.32 mmol) was added and the solution was stirred at room temperature for 1 hour. The solution was filtered to remove dicyclohexylurea and the solvent was evaporated on a rotary evaporator. The residue was filtered through silica gel and eluted with 3: 1 hexane: EtOAc. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.33 (d, J = 8.1 Hz, 2H), 7.27 (multiplex, 1H), 7.13 (t, J = 6.5 Hz, 1H), 6.94 ˜7.00 (multiplex, 2H), 6.73 (s, 1H), 6.55 (d, J = 8.0, 1H), 4.67 (s, 2H), 4.15 (t, J = 6.5 Hz, 2H), 3.93 (s, 2H), 3.10 (s, 3H), 2.42 to 2.50 (multiplex, 4H), 2.28 (s, 3H), 2. 02 to 2.11 (multiplex, 2H), 1.44 to 1.71 (multiplex, 8H).

Example 29: 2- {4- [3-Methyl-3- (nitrosothio) butanoyl] piperazinyl} ethyl 2- {2-[(2,6-dichlorophenyl) methyl] phenyl} acetate 29a. 1- [4- (2-Hydroxyethyl) piperazinyl] -3-methyl-3- (phenylmethylthio) but-1-one 3-methyl-3- (phenylmethylthio) butanoic acid (1 g, 4.6 mmol) and hexachloro a mixture of acetone was dissolved in _CH 2 _Cl 2 (20ml), cooled to -78 ° C.. Triphenylphosphine was added and the mixture was stirred for 30 minutes. Hydroxyethylpiperazine (550 μl, 4.5 mmol) was added dropwise to CH ₂ Cl ₂ (10 ml). Triethylamine (630 μl, 4.5 mmol) was added dropwise to CH ₂ Cl ₂ (10 ml). The cold bath was removed and the solution was stirred for 24 hours. The solvent was evaporated. The crude mixture was poured into 1N HCl (100 ml) and washed twice with 50 ml ether. The aqueous layer was made alkaline with 10% K ₂ CO ₃ in brine. The product was extracted 3 times with 100 ml of EtOAc, dried over Na ₂ SO ₄ and concentrated. The title compound was thus obtained and used immediately in the next reaction. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.18-7.37 (multiplex, 5H), 3.8 (s, 2H), 3.6 (t, J = 5 Hz, 4H), 3.4 (t, J = 5 Hz, 2H), 2.45 to 2.65 (multiplex, 8H), 1.5 (s, 6H).

29b. 1- [4- (2-Hydroxyethyl) piperazinyl] -3-methyl-3-sulfanylbut-1-one Ammonia (100 ml) was condensed in a three-necked flask at −78 ° C. The product of Example 29a was added to the flask with a minimal amount of ether solution. The solution was stirred for 20 minutes. Pear-sized sodium was added until the solution remained blue for well over 10 minutes. The solution was stirred for an additional 30 minutes. The ice bath was removed and ammonia was allowed to evaporate at room temperature. This gave the title compound (600 mg, 55% over 2 steps). ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.63 (t, J = 5 Hz, 4H), 3.52 (t, J = 5 Hz, 2H), 2.63 (s, 2H), 2.38 to 2.57 (Multiple, 6H), 1.51 (s, 6H).

29c. 1- [4- (2-hydroxyethyl) piperazinyl] -3-methyl-3- (Nitorosochio) dissolved but- 1-one tert BuONO (270μl, 2.25mmol) solution in _CH 2 _Cl 2 (5 ml) And cooled to -78 ° C. A solution of the product of Example 29b (430 mg, 1.5 mmol) in MeOH (0.5 ml) and CH ₂ Cl ₂ (10 ml) was added dropwise over 15 minutes. The ice bath was removed and stirring was continued for 30 minutes. Solvent and excess reagent were evaporated. This gave the title compound (400 mg, 97%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 3.63 (t, J = 5 Hz, 4H), 3.47 (t, J = 5 Hz, 2H), 3.27 (s, 2H), 2.44 to 2.60 (Multiple, 6H), 2.04 (s, 6H).

29d. 2- {4- [3-Methyl-3- (nitrosothio) butanoyl] piperazinyl} ethyl 2- {2-[(2,6-dichlorophenyl) methyl] phenyl} acetate Product of Example 29c (400 mg, 1.45 mmol ), {2-[(2,6-dichlorophenyl) amino] benzene} acetic acid (520 mg, 1.7 mmol), DCC (350 mg, 1.7 mmol) and DMAP (50 mg, 0.3 mmol) in CH ₂ Cl ₂ (50 ml). ). The solution was stirred at room temperature for 3 hours. The precipitate was removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel eluting with 1: 1 hexane: EtOAc. The title compound (400 mg, 50%) was thus obtained as a green oil. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.34 (d, J = 8 Hz, 2H), 7.22 (d, J = 8 Hz, 1H), 7.1 to 7.05 (multiplex, 1H), 6.93 -7.01 (multiplex, 2H), 6.84 (s, 1H), 6.53 (d, J = 8Hz, 1H), 4.27 (t, J = 5Hz, 2H), 3.81 (s) 2H), 3.46-3.54 (multiplex, 2H), 3.29-3.37 (multiplex, 2H), 3.22 (s, 2H), 2.63 (t, J = 5 Hz, 2H ) 2.31-2.42 (multiplex, 4H), 2.02 (s, 6H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.0, 167.6, 142.6, 137.6, 130. 8, 129.5, 128.9, 128.0, 124.1, 121.9, 118.1, 62.2, 56.3, 54 8,53.1,52.9,46.0,44.5,41.4,38.6,29.1.

Example 30: {4- [Dicyclopropyl (nitrosothio) methyl] -1-methyl-4-piperidyl} methyl (2S) -2- [6-methoxy (2-naphthyl)] propanoate 30a. Tertiary-butyl 4- (dicyclopropylsulfanylmethyl) -4- (ethoxycarbonyl) piperidinecarboxylate Ethyl N- (t-butoxycarbonyl) isonipecotate (1.06 g, 4.12 mmol) in THF (8 ml) LDA (1.5 M, 2.75 ml, 4.12 mmol) was added dropwise to the stirred solution at −78 ° C. The mixture was stirred for 30 minutes before dicyclopropylthioketone (415 mg, 3.30 mmol) in THF (1 ml) was added. After the addition, the reaction mixture was warmed to room temperature over 2 h, quenched with saturated NH ₄ Cl solution and extracted with EtOAc. The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (1.53 g, 96%) as a viscous oil. It was used in the next step without further purification.

30b. [4- (Dicyclopropylsulfanylmethyl) -1-methyl-4-piperidyl] methane-1-ol Lithium aluminum anhydrous to a stirred THF (10 ml) solution of the product of Example 30a (1.20 g, 3.13 mmol) Product (1M, 9.4 ml, 9.4 mmol) in THF was added dropwise. The mixture was heated to reflux for 15 hours. After cooling to room temperature, the mixture was poured onto Na ₂ SO ₄ · 10H ₂ O, filtered and concentrated. The residue was chromatographed on silica gel eluting with 1: 9 MeOH: CHCl ₃ to give the title compound (0.38 g, 48%) as a white solid. Melting point 66 ° C. ¹ HNMR (300 MHz, CDCl ₃ ) δ 4.00 (s, 2H), 2.7 to 2.8 (multiplex, 2H), 2.30 (s, 3H), 2.1 to 2.2 (multiplex, 3H ) 1.7-1.8 (multiplex, 3H), 1.0-1.1 (multiplex, 2H), 0.4-0.7 (multiplex, 6H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ61 .8, 58.9, 51.9, 46.1, 44.6, 27.9, 16.2, 3.0, 1.0.

30c. [4- (Dicyclopropylsulfanylmethyl) -1-methyl-4-piperidyl] methyl (2S) -2- [6-methoxy (2-naphthyl)] propanoate (2S) -2- [6-methoxy (2- A solution of acid chloride from (naphthyl)] propanoic acid (0.341 g, 1.37 mmo 8 ml) was stirred overnight at room temperature. After dilution with CH ₂ Cl ₂ (30 ml), the mixture was washed with 2M Na ₂ CO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel eluting with 2% MeOH: CHCl ₃ to give the title compound (0.430 g, 81%) as a foam. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.0 to 7.7 (multiplex, 6H), 4.40 (d, J = 16.4 Hz, 1H), 4.22 (d, J = 16.4 Hz, 1H) 3.89 (s, 3H), 3.77 (q, J = 7.4 Hz, 1H), 2.7 to 1.8 (m8H), 2.20 (s, 3H), 1.71 (d , J = 7.4 Hz, 3H), 1.20 (s, 1H), 0.9 to 0.2 (multiplex, 10H).

30d. {4- [Dicyclopropyl (nitrosothio) methyl] -1-methyl-4-piperidyl} methyl (2S) -2- [6-methoxy (2-naphthyl)] propanoate The product of Example 30c (268 mg, 0. To a stirred CH ₂ Cl ₂ (5 ml) solution of 573 mmol) at 0 ° C. were added pyridine (162 μl, 2 mmol) and nitrosonium tetrafluoroborate (81 mg, 0.69 mmol). After stirring for 15 minutes, the reaction mixture was quenched in water (2 ml) and partitioned between CH ₂ Cl ₂ and 1M K ₂ CO ₃ . The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel eluting with EtOAc to give the title compound (259 mg, 91%) as a green solid. Melting point 88 ° C. ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.07-7.70 (multiplex, 6H), 4.63 (d, J = 12.8 Hz, 1H), 4.50 (d, J = 12.8 Hz, 1H) 3.92 (s, 3H), 3.84 (q, J = 7.2 Hz, 1H), 1.7 to 2.8 (multiplex, 8H), 2.21 (s, 3H), 1.57 (D, J = 7.2 Hz, 3H), 0.15-0.75 (multiplex, 10H).

Example 31: 2- {2-[(2,6-dichlorophenyl) amino] phenyl} -1- (2- {methyl [2-methyl-2- (nitrosothio) propyl] amino} ethylthio) ethane-1-one Hydrochloride 31a. Di 1-methyl-1- (1,3-thiazolidin-2-yl) ethyl disulfide 2-[(1,1-dimethyl-2-oxoethyl) disulfanyl] -2-methylpropanal (0.54 g, 2. A stirred mixture of 60 mmol), 2-aminoethaneethiol hydrochloride (0.63 g, 5.5 mmol) and K ₂ CO ₃ (1.0 g) in MeOH (15 ml) was heated to reflux for 1 hour. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give the title compound (diastereomeric mixture) as a colorless liquid (0.85 g, 94%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.77 and 4.75 (2s, 2H), 3.7 to 3.4 (multit, 2H), 2.7 to 3.1 (multit, 6H), 1. 99 (brs, 2H), 1.51 and 1.47 (2s, 12H).

31b. tert-Butyl 2- {1-[(1- {3-[(tert-Butyl) oxycarbonyl] (1,3-thiazolidin-2-yl)}-isopropyl) disulfanyl] -isopropyl} -1,3- Thiazolidine-3-carboxylate The product of Example 31a (7.43 g, 28.6 mmol), di-t-butyl dicarbonate (15.6 g, 71.5 mmol), DMAP (12 mg) and Et ₃ N (20 ml, 143 mmol) in CH ₂ Cl ₂ (100 ml) was stirred at room temperature for 15 hours. After dilution with CH ₂ Cl ₂ (200 ml), the mixture was washed with 1N HCl, dried over Na ₂ SO ₄ , filtered and concentrated. This gave the title compound (12.5 g) as an oil and was used in the next step without further purification.

31c. 2-Methyl-1- [methyl (2-sulfanylethyl) amino] propane-2-thiol Hydrogenated in THF to a stirred solution of the product of Example 31b (2.35 g, 4.48 mmol) in THF (50 ml). Aluminum lithium (1.0 M, 20 ml, 20 mmol) was added dropwise. The mixture was heated to reflux overnight. Upon cooling, the mixture was poured onto Na ₂ SO ₄ .10H ₂ O, filtered and concentrated to give the title compound (0.98 g, 61%) as a colorless liquid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.74 (t, J = 5.9 Hz, 2H), 2.63 (t, J = 5.9 Hz, 2H), 2.48 (s, 2H), 2. 37 (s, 3H), 1.43 and 1.42 (2s, 2H), 1.36 (s, 6H).

31d. 2- {2-[(2,6-dichlorophenyl) amino] phenyl} -1- {2- [methyl (2-methyl-2-sulfanylpropyl) amino] ethylthio} ethane-1-one hydrochloride of Example 31c CH of product (2.58 g, 14.3 mmol), (2-((2,6-dichlorophenyl) amino) benzene) acetic acid (5.09 g, 17.2 mmol) and DCC (3.55 g, 17.2 mmol) ₂ Cl ₂ (60ml) are the solution was stirred for 90 minutes at room temperature. The solid formed during the reaction was removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel eluting with 1: 9 EtOAc: hexane. The free base was converted to its hydrochloride salt by treatment with HCl in ether to give the title compound (8.8 g, 73%). ¹ H NMR (300 MHz, d ₆ -DMSO) δ 6.5-8.2 (multit, 8H), 4.02 (s, 2H), 3.06 (t, J = 6.5 Hz, 2H), 2. 74 (t, J = 6.5 Hz, 2H), 2.63 (s, 2H), 2.40 (s, 3H), 1.38 (s, 6H); ¹³ C NMR (75 MHz, d ₆ -DMSO) ) Δ 198.5, 142.5, 137.6, 130.8, 129.4, 128.7, 128.0, 124.2, 123.9, 121.9, 118.0, 71.5, 58 .7, 47.6, 46.3, 44.2, 30.2, 27.7.

31e. 2- {2-[(2,6-dichlorophenyl) amino] phenyl} -1- (2- {methyl [2-methyl-2- (nitrosothio) propyl] amino} ethylthio) ethane-1-one hydrochloride Examples To a stirred solution of 31d product (0.47 g, 0.951 mmol) in CH ₂ Cl ₂ (20 ml) at −5 ° C. was added t-BuONO (0.132 ml, 1.00 mmol) and the mixture was added to 5 Stir for minutes. The solvent was distilled off to give the desired product as a green solid (0.48 g, 96%). ¹ H NMR (300 MHz, d ₆ -DMSO) δ 6.5 to 7.7 (multit, 8H), 4.01 (s, 2H), 3.09 (s, 2H), 3.00 (t, J = 6.4 Hz, 2H), 2.72 (t, J = 6.4 Hz, 2H), 2.39 (s, 3H), 1.85 (s, 6H); ¹³ C NMR (75 MHz, d ₆ -DMSO) ) Δ 198.6, 142.6, 137.6, 130.9, 129.5, 128.8, 128.1, 124.2, 124.0, 121.9, 118.1, 68.4, 58 .8, 58.7, 47.6, 44.3, 27.4, 26.9.

Example 32: 2- {2-[(2,6-dichlorophenyl) amino] phenyl} -1- [2- (methyl {[(nitrosothio) cyclohexyl] methyl} amino) ethylthio] ethane-1-one 32a. 1-{[Methyl (2-sulfanylethyl) amino] methyl} cyclohexane-1-thiol The title compound was synthesized from the product of Example 2a using a sequence analogous to the preparation of the product of Example 31c. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.88 (t, J = 6.6 Hz, 2H), 2.77 (t, J = 7.7 Hz, 2H), 2.54 (s, 2H), 2. 38 (s, 3H), 1.9 to 1.4 (multit, 12H).

32b. 2- {2-[(2,6-dichlorophenyl) amino] phenyl} -1- (2- {methyl [(sulfanylcyclohexyl) methyl] amino} ethylthio) ethane-1-one The product of Example 32a (2. 44 g, 11.1 mmol), (2-((2,6-dichlorophenyl) amino) benzene) acetic acid (3.29 g, 11.1 mmol) and DCC (2.29 g, 11.1 mmol) in CH ₂ Cl ₂ (60 ml ) The solution was stirred at room temperature for 40 minutes. The solid formed during the reaction was removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel eluting with 1:10 EtOAc: hexanes to give the title compound (1.20 g, 30%) as a white solid. Melting point 55 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.5-7.4 (multit, 8H), 4.04 (s, 2H), 3.08 (t, J = 7.3 Hz, 2H), 2.76 (t, J = 7.3 Hz, 2H), 2.54 (s, 2H), 2.43 (s, 3H), 2.16 (s, 1H), 1.4 to 1.8 ( ^{mult, 10H); 13 C NMR} (75MHz, CDCl 3) δ198.7,142.6,137.6,130.9,129.4,128.8,128.0,124.3,123.9, 121.9, 118.1, 58.9, 52.2, 47.6, 44.6, 37.7, 27.6, 25.9, 22.3.

32c. 2- {2-[(2,6-dichlorophenyl) amino] phenyl} -1- [2- (methyl {[(nitrosothio) cyclohexyl] methyl} amino) ethylthio] ethane-1-one The product of Example 32b ( To a stirred solution of 0.790 g, 1.48 mmol) in CH ₂ Cl ₂ (25 ml) at 0 ° C. was added t-BuONO (200 μl, 1.50 mmol) and the mixture was stirred for another 10 minutes. The solvent was distilled off to give the title compound as a green solid (800 mg, 90%). Melting point 115-129 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.5-7.4 (multit, 8H), 4.00 (s, 2H), 3.19 (s, 2H), 2.96 ( ¹³ C, t, J = 7.8 Hz, 2H), 2.70 (t, J = 7.8 Hz, 2H), 2.37 (s, 3H), 1.4 to 1.7 (multit, 10H); NMR (75MHz, CDCl ₃₎ δ198.5,142.4,137.4,130.7,129.3,128.6,127.9,124.1,123.9,121.8,117.9 68.3, 64.2, 58.8, 47.4, 44.3, 33.9, 27.1, 25.4, 22.0.

Example 33: 4-({Methyl [2-methyl-2- (nitrosothio) propyl] amino} methyl) phenyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate 33a. 4-{[Methyl (2-methyl-2-sulfanylpropyl) amino] methyl} phenyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate The product of Example 5c (2.50 g, 11 0.0 mmol), (2-((2,6-dichlorophenyl) amino) benzene) acetic acid (3.26 g, 11.0 mmol) and DCC (2.24 g, 11.0 mmol) in CH ₂ Cl ₂ (60 ml). Stir at room temperature for 30 minutes. The solid formed during the reaction was removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel eluting with 1: 9 EtOAc: hexanes to give the title compound (5.0 g, 94%) as a colorless liquid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.5 to 7.4 (multit, 8H), 4.03 (s, 2H), 3.67 (s, 2H), 2.77 (s, 2H), 2 .55 (s, 3H), 1.35 (s, 6H).

33b. 4-({Methyl [2-methyl-2- (nitrosothio) propyl] amino} methyl) phenyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate Product of Example 33a (1.28 g To a stirred solution of 2.37 mmol) in CH ₂ Cl ₂ (45 ml) was added t-BuONO (330 μl, 2.49 mmol) and the mixture was stirred for an additional 10 minutes. The solvent was distilled off to give the title compound as a green solid (0.79 g, 90%). Melting point: 126-130 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.5-7.4 (multit, 8H), 4.06 (s, 2H), 3.66 (s, 2H), 3.18 ( s, 2H), 2.30 (s, 3H), 1.92 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.7, 149.5, 142.7, 137.7, 137. 3, 131.0, 129.5, 129.5, 128.82, 128.2, 124.1, 123.9, 122.2, 121.2, 118.5, 68.2, 63.8, 59.1, 44.3, 38.6, 27.2.

Example 34: (2R, 3R) -2,3-dihydroxy-3- {N- [2-methyl-2- (nitrosothio) propyl] carbamoyl} propyl 2- {2-[(2,6-dichlorophenyl) amino ] Phenyl} acetate 34a. [(4R, 5R) -5- (hydroxymethyl) -2,2-dimethyl (1,3-dioxolan-4-yl)]-N- (2-methyl-2-sulfanylpropyl) carboxamide 2,3-O -Isopropylidene-D-erythrone sonolactone (0.16 g, 1.0 mmol), 1-amino-2-methyl-2-propanethiol (0.160 g, 1.52 mmol) and 2-hydroxypyridine (9.5 mg) , 0.1 mmol) in THF (15 ml) was refluxed for 2 hours. After evaporation of the solvent, the resulting solid was purified by recrystallization from EtOAc to give the title compound as white needles (0.30 g, 96%). Melting point 82 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.32 (br, 1 H), 4.67 (d, J = 7.6 Hz, 1 H), 4.59 (multit, 1 H), 3.80 ( td, J = 4.6 and 12.0 Hz, 1H), 3.66 to 3.52 (multit, 3H), 3.21 (dd, J = 5.3 and 13.6 Hz, 1H), 1.76. (Br, 1H), 1.67 (s, 1H), 1.61 (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H), 1.36 (s, 3H) ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.0, 109.4, 76.4, 76.1, 60.8, 51.1, 44.3, 29.7, 29.0, 26.4, 23.9.

34b. [(4R, 5R) -5- (hydroxymethyl) -2,2-dimethyl (1,3-dioxolan-4-yl)]-N- [2-methyl-2- (nitrosothio) propyl] carboxamide Example 34a To a stirred solution of the product of (1.97 g, 7.48 mmol) in CHCl ₃ (50 ml) was added t-BuONO (1.06 ml, 8.0 mmol). After stirring for 10 minutes, the resulting green solution was concentrated to give the title compound (1.95 g, 92%) as a red solid. Melting point 79 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.92-7.35 (multit, 7H), 6.67 (multit, 1H), 6.53 (d, J = 8.0 Hz, 1H), 4.51 ( multit, 1H), 4.31 (multit, 1H), 3.95-4.28 (multit, 4H), 3.90 (s, 2H), 3.88 (s, 2H), 1.86 (s) , 6H).

34c. ((4R, 5R) -2,2-dimethyl-5- {N- [2-methyl-2- (nitrosothio) propyl] carbamoyl} -1,3-dioxolan-4-yl) methyl 2- {2- [ (2,6-Dichlorophenyl) amino] phenyl} acetate The product of Example 34b (1.48 g, 5.06 mmol), (2-((2,6-dichlorophenyl) amino) benzene) acetic acid (1.55 g, 5 0.06 mmol), DCC (1.0 M in CH ₂ Cl ₂ , 5.06 ml) and DMAP (10 mg) in CH ₂ Cl ₂ (40 ml) were stirred at room temperature for 5 hours. The formed solid was removed by filtration. The filtrate was concentrated and the resulting solid was chromatographed on silica gel eluting with 1: 1 EtOAc: hexanes to give the title compound as a green foam (2.1 g, 62%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.90-7.35 (multit, 6H), 6.87 (multit, 1H), 6.54 (d, J = 8.0 Hz, 1H), 4.53- 4.66 (multit, 4H), 4.00 to 4.06 (multit, 3H), 3.82 (multit, 2H), 1.88 (s, 3H), 1.86 (s, 3H) .45 (s, 3H), 1.35 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 171.7, 168.7, 142.7, 137.7, 130.8, 129.4, 128.7, 127.9, 124.0, 123.9, 121.8, 118.2, 110.3, 75.5, 74.9, 63.6, 56.6, 48.9, 38. 2, 26.8, 26.7, 24.5.

34d. (2R, 3R) -2,3-dihydroxy-3- {N- [2-methyl-2- (nitrosothio) propyl] carbamoyl} propyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate A solution of the product of Example 34c (0.57 g, 1.0 mmol) and 2N aqueous HCl (10 ml) in THF (20 ml) was stirred at room temperature for 20 hours. The mixture was poured into water (20 ml) and extracted with EtOAc (25 ml × 3). The combined organic layers were washed with aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel to give the title compound (0.31 g, 68%) as a green solid. Melting point 57-59 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.92-7.5 (multit, 7H), 6.67 (multit, 1H), 6.53 (d, J = 8.0 Hz, 1H) ), 4.51 (multit, 1H), 4.31 (multit, 1H), 3.95-4.28 (multit, 4H), 3.90 (s, 2H), 3.88 (s, 2H) , 1.86 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.1, 172.8, 142.6, 137.6, 130.9, 129.5, 128.9, 124.2 123.7, 122.2, 118.3, 71.7, 69.8, 65.9, 56.6, 49.1, 38.3, 29.9, 26.7.

Example 35: 2- {1- [2-methyl-2- (nitrosothio) propyl] -4-piperidyl} ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate 35a. 2- [1- (2-Methyl-2-sulfanylpropyl) -4-piperidyl] ethane-1-ol 4-piperidineethanol (5.00 g, 38.7 mmol) and the product of Example 8a (3.41 g, 38.7 mmol) of the solvent-free mixture was stirred at 85 ° C. for 4 hours. Crystallization from EtOAc gave the title compound as white needles (6.95 g, 83%). Melting point 42 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.66 (t, J = 6.7 Hz, 2H), 2.86-2.91 (multit, 2H), 2.34 (s, 2H), 2.28 (multit, 2H), 2.03 to 2.25 (br, 1H), 1.60 to 1.63 (multit, 2H), 1.46 to 1.59 (multit, 2H), 32 (multit, 1H), 1.29 (s, 6H), 1.24 to 1.26 (multit, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 71.3, 60.4, 56.3, 46.5, 39.4, 32.8, 31.9, 30.0.

35b. 2- {1- [2-Methyl-2- (nitrosothio) propyl] -4-piperidyl} ethane-1-ol Stirred solution of the product of Example 35a (7.28 g, 28.7 mmol) in MeOH (100 ml). To t-BuONO (3.79 ml, 28.7 mmol) was added. After stirring for 15 minutes, the mixture was concentrated and the residue was partitioned between Na ₂ CO ₃ and EtOAc. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Chromatography on silica gel eluting with 1: 1 EtOAc: hexanes gave the title compound (5.50 g, 90%) as a green oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.58 (t, J = 6.6 Hz, 2H), 2.89 (s, 2H), 2.74 to 2.79 (multit, 2H), 2.54 ( br, 1H), 2.26 (t, J = 11.6 Hz, 2H), 1.81 (s, 6H), 1.56 to 1.51 (multit, 2H), 1.14 to 1.22 ( ^13C NMR (75 MHz, CDCl ₃ ) δ 68.3, 60.1, 59.0, 56.1, 39.1, 32.5, 31.7, 26.8.

35c. 2- {1- [2-Methyl-2- (nitrosothio) propyl] -4-piperidyl} ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate The product of Example 35b (2. 37 g, 9.62 mmol), (2-((2,6-dichlorophenyl) amino) benzene) acetic acid (2.96 g, 10 mmol) and DCC (1.0 M in CH ₂ Cl ₂ , 10 ml) in CH ₂ Cl ₂ ( The mixture was stirred at room temperature for 1 hour and then filtered. The filtrate was concentrated and the residue was chromatographed on silica gel eluting with 1: 1 EtOAc: hexane to give the title compound (4.0 g, 80%) as a green oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.96-7.40 (multit, 7H), 6.60 (d, J = 7.9 Hz, 1H), 4.23 (t, J = 6.7 Hz, 2H) ), 3.86 (s, 2H), 2.97 (s, 2H), 2.83 (d, J = 11.5 Hz, 2H), 2.30 (t, J = 10.8 Hz, 2H), 1.91 (s, 6H), 1.57 to 1.66 (multit, 4H), 1.21 to 1.33 (multit, 4H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.2, 142. 5, 137.6, 130.7, 129.3, 128.7, 127.8, 124.3, 123.9, 121.8, 118.1, 68.2, 63.2, 58.9, 56.0, 38.6, 34.9, 32.3, 32.1, 26.8.

Example 36: {(2S) -1- [2-Methyl-2- (nitrosothio) propyl] pyrrolidin-2-yl} methyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate 36a. [(2S) -1- (2-methyl-2-sulfanylpropyl) pyrrolidin-2-yl] methane-1-ol (S) -2-pyrrolidinemethanol (6.21 g, 61.4 mmol) and of Example 8a A neat mixture of product (5.41 g, 61.4 mmol) was stirred at 80 ° C. for 5 hours. The reaction mixture was chromatographed on silica gel eluting with 1: 1 EtOAc: hexane to give the title compound (9.9 g, 85%) as a colorless liquid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.62 (dd, J = 3.4 and 11.1 Hz, 1H), 3.43 (dd, J = 3.3 and 11.1 Hz, 1H), 3.30 ~ 3.37 (multit, 1H), 2.73-2.79 (multit, 2H), 2.42-2.58 (multit, 2H), 1.67-1.85 (multit, 4H), 1 .39 (s, 3H), 1.36 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 70.1, 67.1, 62.8, 57.6, 46.1, 31.3, 30.9, 26.7, 24.2.

36b. {(2S) -1- [2-Methyl-2- (nitrosothio) propyl] pyrrolidin-2-yl} methane-1-ol The product of Example 36a (9.17 g, 40.6 mmol) in CH ₂ Cl ₂ To a stirred solution in (200 ml) t-BuONO (5.42 ml, 41.0 mmol) was added dropwise. After stirring for 10 minutes, the mixture was washed with aqueous Na ₂ CO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel eluting with 1: 1 EtOAc: hexane to give the title compound (6.73 g, 78%) as a green oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.25 to 3.48 (multit, 3H), 3.16 (d, J = 14.0 Hz, 1H), 2.76 to 2.81 (multit, 1H), 2.46 to 2.55 (multit, 2H), 1.93 (s, 6H), 1.70 to 1.89 (multit, 5H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 67.3, 67. 2, 62.2, 58.2, 57.65, 27.9, 27.7, 26.8, 24.5.

36c. {(2S) -1- [2-Methyl-2- (nitrosothio) propyl] pyrrolidin-2-yl} methyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate Product of Example 36b (6.70 g, 30.7 mmol), - (2 ((2,6-dichlorophenyl) amino) benzene) acetic acid (10.4 g, 35.0 mmol) and DCC _(CH 2 in Cl ₂ 1.0 M, 35 ml) The mixture in CH ₂ Cl ₂ was stirred at room temperature for 3 hours. The solid that formed was removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel eluting with 1: 2 EtOAc: hexanes to give the title compound (5.7 g, 32%) as a green oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.89-7.33 (multit, 7H), 6.54 (d, J = 7.9 Hz, 1H), 4.10 (dd, J = 5.0 and 10 .9 Hz, 1H), 3.97 (dd, J = 6.5 and 10.7 Hz, 1H), 3.79 (s, 2H), 3.39 (d, J = 14.0 Hz, 1H), 3. .16-3.24 (multit, 2H), 2.92-2.97 (multit, 1H), 2.40-2.49 (q, J = 7.8 Hz, 1H), 1.89 (s, 3H), 1.83 (s, 3H), 1.67 to 1.79 (multit, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.3, 142.7, 137.8, 130.8, 129.4, 128.8, 127.9, 124.3, 124.0, 122.0, 118.2, 6 7.9, 67.7, 64.4, 58.3, 57.6, 38.6, 28.3, 27.9, 27.4, 24.0.

Example 37: 2-({4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} ethoxy) ethyl 2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindole- 3-yl} acetate 37a. 2- {2- [4- (2-Methyl-2-sulfanylpropyl) piperazinyl] ethoxy} ethane-1-ol 1- [4- (2-hydroxyethoxy) ethyl] piperazine (1.04 g, 5.97 mmol) And a neat mixture of the product of Example 8a (0.526 g, 6.00 mmol) was stirred at 80 ° C. for 2 hours. Crystallization from EtOAc gave the title compound (1.45 g, 93%) as a yellow solid. Melting point 38 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.60 to 3.71 (multit, 6H), 2.71 (t, J = 4.6 Hz, 4H), 2.55 to 2.60 (multit) , 6H), 2.40 (s, 2H), 1.31 (s, 6H), 2.22 (br, 1H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 71.9, 70.4, 67. 2, 60.9, 57.2, 54.4, 53.2, 45.7, 29.6.

37b. 2- (2- {4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} ethoxy) ethane-1-ol The product of Example 37a (3.85 g, 14.7 mmol) in MeOH (50 ml). To the stirred solution was added 12N aqueous HCl (2.45 ml, 29.4 mmol) followed by t-BuONO (1.99 ml, 15.0 mmol). After 15 minutes, the mixture was concentrated and the residue was partitioned between EtOAC and aqueous Na ₂ CO ₃ . The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (4.10 g, 95%) as a green oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.59-3.70 (multit, 6H), 2.99 (s, 2H), 2.50-2.70 (multit, 11H), 1.88 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 72.2, 67.9, 67.4, 61.7, 58.7, 57.7, 54.8, 53.4, 26.9.

37c. 2-({4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} ethoxy) ethyl 2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} Acetate The product of Example 37b (6.80 g, 23.4 mmol), 2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} acetic acid (9.20 g, 26 mmol) and DCC (5.30 g, 25.7 mmol) in CH ₂ Cl ₂ (100 ml) were stirred at room temperature for 3 h. The solid that formed was removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel eluting with EtOAc to give the title compound (12.0 g, 74%) as a green oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 2.1 Hz) , 1H), 6.87 (d, J = 9.0 Hz, 1H), 6.64 (multit, 1H), 4.25 (t, J = 4.5 Hz, 2H), 3.82 (s, 3H) ), 3.62 to 3.69 (multit, 5H), 3.54 (t, J = 5.8 Hz, 2H), 2.96 (s, 2H), 2.63 (t, J = 4.5 Hz) , 4H), 2.44-2.53 (multit, 8H), 2.37 (s, 2H), 1.86 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.6, 168. 0, 155.9, 139.1, 135.8, 133.8, 131.0, 130.7, 130.5, 129.0, 11 4.8, 112.3, 111.4, 101.3, 68.7, 68.0, 63.9, 58.7, 57.5, 55.5, 55.2, 53.7, 30. 1, 26.9, 13.3.

Example 38: 2- (2- {4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} ethoxy) ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate 38a. 2- (2- {4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} ethoxy) ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate The product of Example 37b (3 .08 g, 10.6 mmol), (2S) -2- (6-methoxy (2-naphthyl)) propanoic acid (2.70 g, 11.6 mmol) and DCC (2.40 g, 11.6 mmol) in CH ₂ Cl _The mixture in ₂ (50 ml) was stirred at room temperature for 3 hours. The solid that formed was removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel eluting with EtOAc to give the title compound (5.4 g, 91%) as a green oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65-7.69 (multit, 3H), 7.38-7.41 (multit, 1H), 7.08-7.13 (multit, 2H), 4. 22 (s, 2H), 3.88 (s, 3H), 3.41 (t, J = 5.7 Hz, 2H), 3.56 (multit, 2H), 2.91 (s, 2H), 2 .55 (multit, 4H), 2.33 to 2.40 (multit, 7H), 1.83 (s, 6H), 1.56 (d, J = 7.1 Hz, 3H); ¹³ C NMR (75 MHz) , CDCl ₃ ) δ 174.2, 157.3, 135.3, 133.4, 129.0, 128.6, 126.8, 125.9, 125.6, 118.7, 105.2, 68. 5, 68.4, 67.8, 63.6, 58.6, 57.3, 54.9, 53.4 45.0, 26.7, 18.3.

Example 39: 4-({4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} methyl) phenyl 2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindole- 3-yl} acetate 39a. 2-Methyl-1-piperazinylpropane-2-thiol A solution of the product of Example 8a (15.5 g, 0.176 mol) and piperazine (30.0 g, 0.50 mol) in THF (200 ml) was stirred for 4 hours. Refluxed. The solvent was evaporated and the crude material was crystallized from 1: 4 EtOAc: hexanes to give the title compound (21 g, 82%) as white flakes. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.85 (t, J = 4.6 Hz, 4H), 2.58 (t, J = 4.6 Hz, 4H), 2.34 (s, 2H) ), 1.29 (s, 6H).

39b. 4-{[4- (2-Methyl-2-sulfanylpropyl) piperazinyl] carbonyl} phenyl acetate The product of Example 39a (2.50 g, 14.4 mol), 4-acetoxybenzoic acid (2.60 g, 14. 4 mmol), DCC (3.00 g, 14.4 mol) and 1-hydroxybenzotriazole (15 mg) in CH ₂ Cl ₂ (100 ml) was stirred for 1 hour. The solid that formed was removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel eluting with 1: 1 EtOAc: hexanes to give the title compound (4.20 g, 88%) as a white solid. Melting point 121 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.39-7.43 (multit, 2H), 7.10-7.14 (multit, 2H), 3.3-3.9 (multit, 4H) ), 2.6-2.8 (multit, 4H), 2.41 (s, 2H), 2.29 (s, 3H), 1.30 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃₎ ) Δ 168.6, 168.2, 151.0, 132.7, 127.9, 121.1, 70.4, 54.7, 45.5, 29.6, 20.5.

39c. 4-{[4- (2-Methyl-2-sulfanylpropyl) piperazinyl] methyl} phenol To a solution of the product of Example 39b (1.00 g, 29.7 mmol) in THF (20 ml) was added lithium aluminum hydride in THF. (1.0 M, 6.0 ml, 6 mmol) was added dropwise. The mixture was heated to reflux for 1 hour. The mixture was poured over Na ₂ SO ₄ · 10H ₂ O, filtered and concentrated. The resulting material was purified by crystallization from EtOAc to give the title compound (0.81 g, 98%) as a white bowl. Melting point 81 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.07 (d, J = 5.5 Hz, 2H), 6.61 (d, J = 5.5 Hz, 2H), 3.45 (s, 2H ), 2.7-2.8 (br, 4H), 2.5-2.6 (br, 4H), 2.35 (s, 2H), 1.28 (s, 6H); ¹³ C NMR ( 75 MHz, CDCl ₃ ) δ 156.0, 131.1, 127.0, 115.7, 70.8, 62.4, 54.5, 53.1, 46.3, 30.1.

39d. 4-({4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} methyl) phenol The product of Example 39c (0.37 g, 13 mmol) and 12N aqueous HCl (0.22 ml, 26 mmol) in MeOH ( To a stirred solution at 0 ° C. in 10 ml) was added t-BuONO (0.20 ml, 15 mmol). After 10 minutes, the mixture was partitioned between aqueous NaHCO ₃ and CH ₂ Cl ₂ . The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel eluting with 1: 9 MeOH: EtOAc to give the title compound (0.38 g, 98%) as a green oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.05 (d, J = 8.4 Hz, 2H), 6.58 (d, J = 8.4 Hz, 2H), 3.43 (s, 2H), 2. 95 (s, 2H), 2.4 to 2.7 (multit, 8H), 1.85 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 155.8, 131.1, 127.1, 115.7, 67.9, 62.4, 58.7, 54.5, 53.0, 26.9.

39e. 4-({4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} methyl) phenyl 2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} Acetate The product of Example 39d (0.38 g, 0.0013 mol), 2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} acetic acid (0.47 g, 13 mmol) and DCC (0.27 g, 13 mmol) in CHCl ₃ (10 ml) were stirred at room temperature for 30 min. The solid that formed was removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel eluting with 2: 1 hexane: EtOAc to give the title compound (0.49 g, 62%) as a green oil which solidified on standing. Melting point 90-92 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.28 (d , J = 8.4 Hz, 2H), 7.1-6.8 (multit, 4H), 6.68 (dd, J = 2.4 and 9.0 Hz, 1H), 3.88 (s, 2H) 3.81 (s, 3H), 3.45 (s, 2H), 2.96 (s, 3H), 2.6 to 2.7 (multit, 4H), 2.43 (s, 3H), 2.2-2.4 (multit, 4H), 1.85 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 169.1, 168.0, 156.0, 149.6, 139.1 136.0, 135.4, 133.7, 131.0, 130.7, 130.4, 130.0, 128.9, 121. 114.8, 111.9, 111.6, 101.1, 67.9, 62.0, 58.7, 55.5, 55.1, 53.0, 30.3, 26.8, 13 .3.

Example 40: 5-({4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} carbonyl) -2-pyridyl 2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2- Methyl indol-3-yl} acetate 40a. 6-Hydroxy (3-pyridyl) 4- (2-methyl-2-sulfanylpropyl) piperazinyl ketone 6-hydroxypyridine-3-carboxylic acid (5.68 g, 40.86 mmol) and the product of Example 39a ( To a stirred suspension of 7.82 g (44.9 mmol) in CH ₂ Cl ₂ (80 ml) was added HOBt (55 mg) followed by DCC (9.25 g, 44.90 mmol). The reaction mixture was stirred overnight at room temperature. Filter to remove solids and evaporate the filtrate to give the crude material, which is subjected to column chromatography, eluting with 1: 9 MeOH: CH ₂ Cl ₂ to purify the title compound (9. 0 g, 30.51 mmol, 74.7%) was obtained as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.61 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 2.4 and 9.4, 1H), 6.56 (d, J = 9.4, 1H), 3.56 to 3.60 (m, 4H), 2.64 to 2.68 (m, 4H), 2.42 (s, 2H), 1.31 (s, 6H) ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.5, 164.8, 141.0, 136.1, 119.8, 115.2, 71.0, 55.3, 46.1, 30.2 .

40b. 6-Hydroxy (3-pyridyl) -4- [2-methyl-2- (nitrosothio) propyl] piperazinyl ketone To a stirred ice-cold solution of the product of Example 40a in CH ₂ Cl ₂ (100 ml) trifluoroacetic acid (4.7 ml, 61.0 mmol) was added dropwise. Then t-BuONO (3.84 g, 33.51 mmol) was added. The reaction mixture was kept cold for 1 hour and then poured into saturated Na ₂ CO ₃ . The aqueous layer was extracted twice with CH ₂ Cl ₂ . The combined organic extracts were dried over Na ₂ SO ₄ and evaporated to give the title compound as a green solid that was used in the next step without further purification. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.58 (d, J = 2.3 Hz, 1H), 7.48 (dd, J = 2.5 and 9.4, 1H), 6.49 (d, J = 9.4, 1H), 3.45 to 3.50 (m, 4H), 2.97 (s, 2H), 2.55 to 2.60 (m, 4H), 1.82 (s, 6H) ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.4, 164.5, 140.7, 136.2, 119.6, 114.9, 67.9, 58.4, 55.0, 45.5 (Br), 26.8.

40c. 5-({4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} carbonyl) -2-pyridyl 2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindole-3 -Yl} acetate 2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} acetic acid chloride (1.15 g, 3.07 mmol) in CH ₂ Cl ₂ ( To a stirred ice-cold solution in 20 ml) was added Et ₃ N (0.47 ml, 3.38 mmol) followed by the product of Example 40b (995 mg, 3.07 mmol). This was followed by the addition of DMAP (20 mg). The reaction was stirred at room temperature for 2 hours. The solvent is evaporated and the residue is passed through a short silica gel column eluting with 1: 1 EtOAc: hexanes to give the title compound (0.99 g, 1.49 mmol, 49%) as a sticky green solid. It was. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.41 (d, J = 2.2, 1H), 7.88 (dd, J = 2.4 and 8.3, 1H), 7.61-7.67 (M, 2H), 7.42-7.47 (m, 2H), 7.03-7.10 (m, 2H), 6.89 (d, J = 9.1, 1H), 6.67 (Dd, J = 2.5 and 9.1, 1H), 3.95 (s, 2H), 3.82 (s, 3H), 3.30-3.79 (m, 4H), 3.02 (S, 2H), 2.55 to 2.66 (m, 4H), 2.42 (s, 3H), 1.87 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 168.5, 168.2, 166.7, 158.3, 156.1, 147.1, 139.28, 138.8, 136.3, 133.7, 131.1, 130.8, 130 .3, 130.1, 129.1, 116.1, 114.9, 111.8, 111.5, 111.25, 101.1, 68.0, 58.4, 55.7, 55.0 30.4, 26.9, 13.4.

Example 41 2-({2-[(2S) -2- (6-methoxy (2-naphthyl)) propanoyloxy] ethyl} {[(nitrosothio) cyclohexyl] methyl} amino) acetic acid 41a. tert-butyl 2-({[({[({[(tert-butyl) oxycarbonyl] methyl} (2-hydroxyethyl) amino) methyl] cyclohexyl} disulfanyl) cyclohexyl] methyl} (2-hydroxyethyl) amino ) Acetate The product of Example 2b (13.0 g, 34.57 mmol) was dissolved in CH ₃ CN (100 ml) and tert-butyl bromoacetate (10.2 ml, 69.03 mmol) and solid K ₂ CO _3. (23 g) was added sequentially. The resulting suspension was stirred at room temperature for 12 hours. Filtered to remove solids and washed with CH ₃ CN (50 ml). The filtrate was concentrated and the residue was chromatographed on silica gel eluting with 1: 2 EtOAc: hexanes to give the title compound (18.2 g, 87.5%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.55 to 3.61 (m, 4H), 3.40 (s, 4H), 2.86 to 2.88 (m, 8H), 1.47 (s, 18H), 1.20-1.67 (m, 20H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.0, 81.3, 65.8, 59.8, 59.7, 58.0, 56 .2, 33.2, 28.1, 25.7, 22.3; mass spectrum (API-TIS), m / z 605 (MH ^<+> ).

41b. 2-({[(tert-butyl) oxycarbonyl] methyl} {[({[({[(tert-butyl) oxycarbonyl] methyl} {2-[(2S) -2- (6-methoxy (2- Naphthyl)) propanoyloxy] ethyl} amino) methyl] cyclohexyl} disulfanyl) cyclohexyl] methyl} amino) ethyl (2S) -2- (6-methoxy-2-naphthyl) propanoate in CH ₂ Cl ₂ (50 ml) DCC (4.9 g, 23.8 mmol) was added to the product of Example 41a (6.0 g, 9.92 mmol), (2S) -2- (6-methoxy (2-naphthyl)) propanoic acid (4.56 g). , 19.8 mmol) and DMAP (0.35 g) in CH ₂ Cl ₂ (50 ml) at 0 ° C. and added dropwise. The resulting suspension was stirred at room temperature for 1 hour. Filtered to remove the precipitate and washed with CH ₂ Cl ₂ (2 × 25 ml). The filtrate was concentrated to give a green oil that was chromatographed on silica gel eluting with 1: 1 EtOAc: hexanes to give the title compound (9.8 g, 96%) as a white foam. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65-7.69 (multit, 6H), 7.38 (dd, J = 1.7 and 8.8 Hz, 2H), 7.08-7.13 (multit) , 4H), 3.87 (s, 6H), 3.81 to 4.06 (multit, 2H), 3.40 (brs, 4H), 2.91 (multit, 4H), 2.69 (s) , 4H), 1.56 (d, J = 7.1 Hz, 6H), 1.03 to 1.57 (multit, 20H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.5, 174.0, 157 .6, 135.3, 133.7, 129.2, 128.9, 127.2, 126.1, 126.0, 119.0, 105.6, 66.4, 62.6, 58.5 , 56.0, 55.7, 55.3, 45.4, 33.0, 25.4, 22. , 18.4; mass spectrum (API-TIS), m / z 917 (MH +).

41c. 2-({[({[((carboxymethyl) {2-[(2S) -2- (6-methoxy (2-naphthyl)) propanoyloxy] ethyl} amino) methyl] cyclohexyl} disulfanyl) cyclohexyl] Methyl} {2-[(2S) -2- (6-methoxy (2-naphthyl)) propanoyloxy] ethyl} amino) acetic acid The product of Example 41b (9.4 g, 9.13 mmol) was added to CH ₂ Cl ₂ (25 ml) and then TFA (25 ml) was added. The resulting solution was stirred at room temperature for 12 hours. The mixture was poured onto crushed ice made basic with concentrated NH ₄ OH (40 ml). The aqueous product was extracted with EtOAc (3 × 50 ml). The combined organic layers were dried over Na ₂ SO ₄ and filtered. The solvent was evaporated and the residue was chromatographed on silica gel eluting with 1:19 MeOH: CH ₂ Cl ₂ to give the title compound (8.3 g, 88%) as a white foam. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.4 Hz, 4H), 7.43 (d, J = 8.4 Hz, 4H), 6.94 (d, J = 2.3 Hz) , 2H), 6.84 (d, J = 9.0 Hz, 2H), 6.63 (dd, J = 2.4 and 9.0 Hz, 2H), 4.16 (multit, 4H), 3.79. (S, 6H), 3.65 (br s, 4H), 3.40 (br s, 4H), 3.01 (multit, 4H), 2.81 (s, 4H), 2.34 (s, 6H), 1.18 to 1.57 (m, 20H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.7 (2C), 168.2, 156.0, 139.2, 136.0, 133. 8, 131.1, 130.8, 130.6, 129.1, 114.9, 112.2, 111.5, 101 4, 65.8, 63.1, 58.2, 56.0, 55.7 (2C), 33.1, 30.1, 25.6, 22.1, 13.3; mass spectrum (API- TIS), m / z 1173 (MH ^<+> ).

41d. 2-({2-[(2S) -2- (6-methoxy (2-naphthyl)) propanoyloxy] ethyl} {[(nitrosothio) cyclohexyl] methyl} amino) acetic acid The product of Example 41c (6. 2 g, 6.76 mmol) was dissolved in HOAc (30 ml) and powdered zinc (12 g) was added. The resulting suspension was stirred at room temperature for 12 hours. Filter to remove inorganic solids and wash with HOAc (25 ml). The filtrate was basified with concentrated NH ₄ OH in crushed ice (100 g) and extracted with EtOAc (3 × 50 ml). The combined organic extracts were dried over _Na 2 SO _4, and filtered. The solvent was distilled off to give a white foam (4 g) which was subsequently dissolved in a mixture of CH ₂ Cl ₂ (20 ml) and MeOH (10 ml) and cooled to 0 ° C. Concentrated HCl (1.5 ml) was added via syringe followed by 90% tert-butyl nitrite (1.1 ml, 8.7 mmol). The resulting green solution was stirred at 0 ° C. for 15 minutes and then poured onto crushed ice (about 15 g). 10% Na ₂ CO ₃ (10 ml) was added until the mixture was slightly basic. This mixture was extracted with EtOAc (3 × 50 ml). The combined organic extracts were dried over Na ₂ SO ₄ and filtered. The solvent was removed and the residue was chromatographed on silica gel eluting with 1: 1 EtOAC: hexane to give the title compound (2.1 g, 32%) as a green oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.74-7.70 (m, 3H), 7.37 (dd, J = 1.7 and 8.4 Hz, 1H), 4.08-4.14 (multit) , 2H), 3.89 (s, 3H), 3.81 (q, J = 7.1 Hz, 1H), 3.38 (s, 2H), 3.34 (s, 2H), 2.90- 2.97 (multit, 2H), 2.30 to 2.34 (multit, 2H), 1.55 (d, J = 3.94 (t, J = 5.2 Hz, 2H), 1.15 to 1 .82 (m, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.7, 174.4, 157.6, 135.3, 133.7, 129.3, 128.9, 127.2, 126 .1, 126.0, 119.0, 105.6, 67.1, 63.9, 62.6, 57.7, 55.3, 55.2, 45.4, 34.2, 25.4, 21.9, 18.3; mass spectrum (API-TIS), m / z 489 (MH ^<+> ).

Example 42: 2-{[2- (2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} acetyloxy) ethyl] {[(nitrosothio) cyclohexyl] Methyl} amino} acetic acid 42a. 2-{{[(tert-butyl) oxycarbonyl] methyl} [({[({{[(tert-butyl) oxycarbonyl] methyl} [2- (2- {1-[(4-chlorophenyl) carbonyl] -5-Methoxy-2-methylindol-3-yl} acetyloxy) ethyl] amino} methyl) cyclohexyl] disulfanyl} cyclohexyl) methyl] amino} ethyl 2- {1-[(4-chlorophenyl) carbonyl] -5 DCM (8.8 g, 42.5 mmol) in -methoxy-2-methylindol-3-yl} acetate CH ₂ Cl ₂ (50 ml) was replaced with the product of Example 41a (5.5 g, 9.1 mmol), 2- {1-[(chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} acetic acid (6.5 g, 18 16 mmol) and was added dropwise to a stirred solution of _CH 2 _Cl 2 (60ml) in 0 ℃ of DMAP (0.25 g). The resulting suspension was stirred at room temperature for 1 hour. Filtered to remove the precipitate and washed with CH ₂ Cl ₂ (2 × 25 ml). Concentrate the filtrate to give a green oil, which is chromatographed on silica gel eluting with 1: 1 EtOAc: hexanes to give the title compound (8.3 g, 71.5%) as a white foam. It was. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.66 (d, J = 8.4 Hz, 4H), 7.45 (d, J = 8.4 Hz, 4H), 6.96 (d, J = 2.3 Hz) , 2H), 6.85 (J = 9.0 Hz, 2H), 6.65 (dd, J = 2.5 and 9.0 Hz, 2H), 4.18 (t, J = 5.8 Hz, 4H) 3.82 (s, 6H), 3.66 (s, 4H), 3.39 (s, 4H), 3.03 (t, J = 5.9 Hz, 4H), 2.85 (s, 4H) ), 2.37 (s, 3H), 1.45 (s, 18H), 1.38 to 1.65 (m, 20H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.1, 170.7, 156.0, 139.1, 135.8, 133.9, 131.1, 130.7, 130.6, 129.0, 114.9, 112. 5, 111.6, 101.3, 80.9, 65.4, 63.7, 57.5, 56.0, 55.6, 54.8, 32.8, 30.2, 28.2, 25.7, 22.3, 13.3; mass spectrum (API-TIS), m / z 1285 (MH ^<+> ).

42b. 2-{[({[({(carboxymethyl) [2- (2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-yl} acetyloxy) ethyl] amino} methyl ) Cyclohexyl] disulfanyl} cyclohexyl) methyl] [2- (2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} acetyloxy) ethyl] amino} acetic acid The product of Example 42a (8.3 g, 6.46 mmol) was dissolved in CH ₂ Cl ₂ (20 ml) and then TFA (10 ml) was added. The resulting solution was stirred at room temperature for 12 hours and then poured onto crushed ice made basic with concentrated NH ₄ OH (20 ml). The aqueous layer was extracted with EtOAc (3 × 50 ml). The combined organic layer extracts were dried over Na ₂ SO ₄ and filtered. The solvent was removed and the residue was chromatographed on silica gel eluting with 1: 9 MeOH: CH ₂ Cl ₂ to give the title compound (4.8 g, 64%) as a white foam. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.4 Hz, 4H), 7.43 (d, J = 8.4 Hz, 4H), 6.94 (d, J = 2.3 Hz) , 2H), 6.84 (d, J = 9.0 Hz, 2H), 6.63 (dd, J = 2.4 and 9.0 Hz, 2H), 4.16 (multit, 4H), 3.79. (S, 6H), 3.65 (br s, 4H), 3.40 (br s, 4H), 3.01 (multit, 4H), 2.81 (s, 4H), 2.34 (s, 6H), 1.18 to 1.57 (m, 20H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.7 (2C), 168.2, 156.0, 139.2, 136.0, 133. 8, 131.1, 130.8, 130.6, 129.1, 114.9, 112.2, 111.5, 101 4, 65.8, 63.1, 58.2, 56.0, 55.7 (2C), 33.1, 30.1, 25.6, 22.1, 13.3; mass spectrum (API- TIS), m / z 1173 (MH ^<+> ).

42c. 2-{[2- (2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} acetyloxy) ethyl] {[(nitrosothio) cyclohexyl] methyl} amino} Acetic acid The product of Example 42b (4.50 g, 3.83 mmol) was dissolved in HOAc (22 ml) and powdered zinc (9 g) was added. The resulting suspension was stirred at room temperature for 12 hours. Filtered to remove solids and washed with HOAc (25 ml). The filtrate was basified using concentrated NH ₄ OH in crushed ice (100 g) and extracted with EtOAc (3 × 50 ml). The combined organic layers were dried over Na ₂ SO ₄ and filtered. The solvent was distilled off to give a white foam (4 g) which was subsequently dissolved in a mixture of CH ₂ Cl ₂ (10 ml) and MeOH (35 ml) and cooled to 0 ° C. Concentrated HCl (5 ml) was added followed by 90% tert-butyl nitrite (1 ml, 8.2 mmol). The resulting green solution was stirred at room temperature for 15 minutes and then poured onto crushed ice (ca. 10 g). 10% Na ₂ CO ₃ (10 ml) was added until the mixture was basic and the aqueous mixture was extracted with EtOAc (3 × 50 ml). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed on silica gel eluting with 1: 1 EtOAc: hexanes to give the title compound (2.5 g, 53%) as a green oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.68 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 2.3 Hz) , 1H), 6.87 (d, J = 9.0 Hz, 1H), 6.67 (dd, J = 2.5 and 9.0 Hz, 1H), 4.08 (t, J = 5.3 Hz, 2H), 3.85 (s, 3H), 3.67 (s, 2H), 3.43 (s, 2H), 3.94 (t, J = 5.2 Hz, 2H), 2.38-2 .47 (multit, 2H), 2.38 (s, 3H), 1.37 to 1.96 (m, 8H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 173.7, 170.6, 168.4 156.1, 139.3, 136.1, 133.9, 131.2, 130.8, 130.6, 129.1, 115.1, 1 12.2, 111.7, 101.3, 67.4, 63.9, 62.8, 58.2, 55.7, 34.5, 30.1, 25.5, 22.0, 13. 4; Mass spectrum (API-TIS), m / z 616 (MH ^<+> ).

Example 43: 2- (Methyl {1- [2-methyl-2- (nitrosothio) propyl] (4-piperidyl)} amino) ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate 43a . 1- (2-Methyl-2-sulfanylpropyl) piperidin-4-one 1- (8-aza-1,4-dioxaspiro [4.5] dec-8-yl) -2-methylpropane-2-thiol ( Synthesis, July 1999, 1106) (1.15 g, 4.98 mmol) in a stirred solution of THF (12 ml) was added 6N HCl (12 ml). The mixture was heated at 70 ° C. overnight and then poured into saturated Na ₂ CO ₃ . This mixture was extracted with EtOAc. The combined organic extracts were dried over Na ₂ SO ₄ and evaporated. The residue was dissolved in EtOAc and acidified by addition of HCl / EtOAc until no more solid was formed. The solvent was decanted and the solid was then partitioned between EtOAc and saturated Na ₂ CO ₃ . The aqueous layer was extracted with EtOAc and the combined organic extracts were dried over Na ₂ SO ₄ and evaporated to give the title compound (0.90 g, 4.81 mmol, 97%) as a green oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.96 (t, J = 6.0, 4H), 2.52 (s, 2H), 2.41 (t, J = 6.0, 4H), 34 (s, 6H).

43b. 2- {Methyl [1- (2-methyl-2-sulfanylpropyl) (4-piperidyl)] amino} ethane-1-ol The product of Example 43a (931 mg, 4.98 mmol) in CH ₂ Cl ₂ (20 ml ) 2- (Methylamino) ethanol (748 mg, 9.96 mmol) was added to the solution. Then sodium triacetoxyborohydride (3.17 g, 14.96 mmol) was added. The mixture was poured into water and extracted with CH ₂ Cl ₂ . The combined organic extracts were dried over Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography eluting with 1: 9 MeOH: CH ₂ Cl ₂ to give the title compound as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.53 (t, J = 5.4, 2H), 2.90-2.98 (m, 2H), 2.59 (t, J = 5.4, 2H) ), 2.19-2.40 (m, 4H), 2.32 (s, 2H), 2.25 (s, 3H), 1.49-1.66 (m, 4H), 1.26 ( ¹³ C NMR (75 MHz, CDCl ₃ ) δ 61.4, 58.0, 55.7, 54.6, 46.4, 36.9, 30.0, 28.2.

43c. 2- (Methyl {1- [2-methyl-2- (nitrosothio) propyl] (4-piperidyl)} amino) ethane-1-ol Product of Example 43b (250 mg, 1.02 mmol) in CH ₂ Cl ₂ Trifluoroacetic acid (233 mg, 2.04 mmol) was added dropwise to an ice cold solution in (10 ml). Then t-BuONO was added and the reaction was kept cold for 30 minutes. The reaction mixture was then washed with saturated Na ₂ CO ₃ . The organic layer was dried over Na ₂ SO ₄ and evaporated to give the title compound as a green oil. This product was used in the next step without further purification. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.52 (t, J = 5.4, 2H), 2.94 (s, 2H), 2.83 to 2.90 (m, 2H), 2.57 ( t, J = 5.4, 2H), 2.29 to 2.36 (m, 3H), 2.22 (s, 2H), 1.85 (s, 6H), 1.49 to 1.62 ( m, 4H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 67.9, 61.2, 58.9, 58.1, 55.8, 54.5, 36.9, 28.2, 26.8.

43d. 2- (Methyl {1- [2-methyl-2- (nitrosothio) propyl] (4-piperidyl)} amino) ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate Formation of Example 43c To a solution of the product (275 mg, 1.02 mmol) in CH ₂ Cl ₂ (10 ml), (2S) -2- (6-methoxy (2-naphthyl)) propanoic acid (258 mg, 1.12 mmol) and DCC (232 mg, 1 .12 mmol) was added. The mixture was stirred at room temperature for 2 hours. Filtered to remove solids and evaporated the solvent. The residue was purified by column chromatography eluting with 1: 4 EtOAc: hexane to give the title compound as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.94-7.98 (m, 3H), 7.67-7.70 (m, 1H), 7.38-7.43 (m, 2H), 4. 40 to 4.45 (m, 2H), 4.18 (s, 3H), 4.09 to 4.17 (m, 1H), 3.15 (s, 2H), 3.01 to 3.07 ( m, 2H), 2.89 (t, J = 5.9, 2H), 2.50 (s, 3H), 2.43 to 2.53 (m, 2H), 2.11 (s, 6H) , 1.84 (d, J = 7.1, 3H), 1.62-1.82 (m, 4H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.4, 157.5, 133.6, 133.5, 129.1, 128.8, 127.0, 126.1, 125.8, 118.8, 105.4, 67.7, 63.1, 60.7, 58.8 55.4, 55.1, 51.6, 45.3, 38.4, 28.1, 27.9, 26.7, 18.5.

Example 44: 3-{(4S) -4- [1-methyl-1- (nitrosothio) ethyl] -2-oxo-1,3-oxazolidin-3-yl} propyl (2S) -2- (6- Methoxy (2-naphthyl)) propanoate 44a. (2S) -2-Amino-3-methyl-3-[(2,4,6-trimethoxyphenyl) methylthio] butanoic acid (2S) -2-amino-3-methyl-3-sulfanylbutanoic acid (5. 0 g, 703 mmol) in CH ₂ Cl ₂ (150 ml) was cooled to 0 ° C. Trifluoroacetic acid (54 ml, 703 mmol) was added dropwise over 5 minutes. 2,4,6-Trimethoxybenzyl alcohol (6.64 g, 34 mmol) in CH ₂ Cl ₂ (137 ml) was added dropwise with stirring at 0 ° C. Stirring was continued for 1 hour at 0 ° C. and 2 hours at room temperature, the solvent was removed in vacuo, and the residue was dried under high vacuum for 3 hours. The crude red solid was crystallized from 1: 1: 1 CH ₂ Cl ₂ : MeOH: EtOAc to give 10.5 g (95%) of the title compound as a white solid, which was purified without further purification. Used in the process. ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.10 (s, 2H), 3.84 (s, 6H), 3.76 (s, 3H), 3.40 to 4.10 (multit, 3H), 1 .69 (s, 3H), 1.23 (s, 3H); Mass spectrum (API-TIS) m / z 330 (M + H).

44b. (2S) -2-Amino-3-[(2,4,6-trimethoxyphenyl) methylthio] butan-1-ol A stirred solution of the product of Example 44a (10.5 g, 32 mmol) in THF (80 ml). To the solution was added lithium aluminum hydride (1M in THF, 64 ml, 64 mmol) dropwise at 0 ° C. under nitrogen. The resulting solution was stirred at 0 ° C. for 1 hour and then at room temperature for 2 hours. Excess reducing agent was carefully destroyed by adding Na ₂ SO ₄ · 10H ₂ O dropwise at 0 ° C. The granular white precipitate was removed by filtration and washed with 30% MeOH in CH ₂ Cl ₂ . The combined filtrates were dried over Na ₂ SO ₄ , filtered and evaporated to give 7.6 g (76%) of the title compound as a yellow oil, which was used in the next step without further purification. . ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.10 (s, 2H), 3.80 (s, 6H), 3.77 (s, 3H), 3.74 (s, 2H), 3.60-3 .40 (multit, 2H), 3.36 to 3.43 (multit, 1H), 2.93 to 2.97 (m, 1H), 1.45 (s, 3H), 1.30 (s, 3H) ); Mass spectrum (API-TIS) m / z 316 (M + H).

44c. (4S) -4- [1-Methyl-1- (2,4,6-trimethoxyphenylthio) ethyl] -1,3-oxazolidine-2-one
A mixture of K ₂ CO ₃ (0.33 g, 2.4 mmol), diethyl carbonate (50 ml) and the product of Example 44b (7.6 g, 24 mmol) was heated at 100 ° C. for 24 hours. The solvent was distilled off and the resulting light brown slurry was cooled to room temperature, diluted with CH ₂ Cl ₂ and filtered to remove most of the remaining K ₂ CO ₃ . The filtrate was evaporated in vacuo and the residue was chromatographed on silica gel eluting with 1: 1 EtOAc: hexanes to give 2.6 g (32%) of the title compound as a viscous yellow oil. Unreacted product 44b can be recovered by eluting with 20% MeOH in CH ₂ Cl ₂ . ¹ H NMR (300 MHz, CDCl ₃ ) δ 5.86 (s, 2H), 5.75 (br s, 1H), 4.36 to 4.43 (multit, 1H), 4.23 to 4.29 (multit) , 1H), 4.04 to 4.10 (multit, 1H), 3.86 (s, 6H), 3.83 (s, 2H), 3.81 (s, 3H), 1.30 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 160.7, 159.4, 158.7, 106.1, 90.8, 66.4, 59.4, 56.0, 55.5, 47. 1,23.9,22.3,20.3,14.3; mass spectrum (API-TIS) m / z 342 (M + H), 359 (M + NH 4), 364 (M + Na).

44d. 3-Bromo-1- (1,1,2,2-tetramethyl-1-silapropoxy) propane imidazole (0.52 g, 7.6 mmol) and t-butyldimethylchlorosilane (5.80 g, 38 mmol) -Bromo-3-propanol (5.35 g, 38 mmol) was added continuously to a solution of dry THF (10 ml) at room temperature. The resulting suspension was stirred at room temperature for 20 hours. EtOAc (25 ml) was added. The solution was washed with water, dried over Na ₂ SO ₄ , filtered and concentrated at room temperature under vacuum. The residue was chromatographed on silica gel eluting with 1:10 EtOAc: hexanes to give 2.1 g (22%) of the title compound as a colorless volatile liquid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.74 (t, J = 5.7 Hz, 2H), 3.52 (t, J = 6.5 Hz, 2H), 2.02 to 2.06 (multit, 2H) ), 0.90 (s, 9H), 0.07 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 60.6, 35.7, 30.8, 26.1, −5.2.

44e. (4S) -4- {1-Methyl-1-[(2,4,6-trimethoxyphenyl) methylthio] ethyl} -3- [3- (1,1,2,2-tetramethyl-1-sila Propoxy) propyl] -1,3-oxazolidine-2-one A solution of the product of Example 44c (2.18 g, 6.4 mmol) in dry DMF (40 ml) under NaH (0.32 g, 12.8 mmol) under nitrogen. Was added dropwise. The resulting suspension was stirred at room temperature for 20 minutes to give a reddish brown solution. The product of Example 44d (1.94 g, 7.7 mmol) in dry DMF (10 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 hours and the solvent was distilled off. The residue was partitioned between EtOAc: H ₂ O and the organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over Na ₂ SO ₄ and filtered. The residue after evaporation of the solvent was chromatographed on silica gel eluting with 1:19 to 1: 3 EtOAc: hexane to give 1.66 g (51%) of the title compound as a white foam. ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.11 (s, 2H), 4.38 to 4.42 (multit, 1H), 4.05 to 4.11 (multit, 1H), 3.93 to 3. 96 (multit, 1H), 3.83 (s, 6H), 3.80 (s, 3H), 3.77 (s, 2H), 3.65 (t, J = 6.1 Hz, 2H), 3 .58 to 3.71 (multit, 1H), 3.34 to 3.44 (multit, 1H), 1.66 to 1.96 (multit, 2H), 1.56 (s, 3H), 1.24 (S, 3H), 0.89 (s, 9H), 0.04 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 160.7, 159.5, 158.7, 107.0, 90 .8, 65.7, 61.7, 60.6, 55.9, 55.4, 48.3, 42.6, 30.3, 2 6.8, 26.0, 22.2, 20.4, 18.4, -5.3; Mass spectrum (API-TIS) m / z 514 (M + H), 536 (M + Na).

44f. (4S) -3- (3-hydroxypropyl) -4- {1-methyl-1-[(2,4,6-trimethoxyphenyl) methylthio] ethyl} -1,3-oxazolidine-2-one tetrabutyl Ammonium fluoride (1M solution in THF, 4.0 ml, 4 mmol) was added dropwise at 0 ° C. to a solution of the product of Example 44e (1.66 g, 3.2 mmol) in THF (20 ml). The resulting solution was stirred at 0 ° C. for 3 hours. The residue after evaporation of the solvent was chromatographed on silica gel eluting with 1: 1 EtOAc: CH ₂ Cl ₂ to give 1.05 g (81%) of the title compound as a colorless viscous oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.12 (s, 2H), 4.28 to 4.33 (multit, 1H), 4.12 to 4.19 (multit, 1H), 3.95 to 3. 98 (multit, 1H), 3.83 (s, 6H), 3.80 (s, 3H), 3.78 (s, 2H), 3.54 to 3.70 (multit, 4H), 2.57 (Br s, 1H), 1.78-1.85 (multit, 2H), 1.49 (s, 3H), 1.30 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 160.9 160.8, 158.7, 106.8, 90.9, 65.7, 62.0, 59.1, 56.0, 55.5, 47.6, 41.7, 30.3, 25 .6, 23.2, 20.6; mass spectrum (API-TIS) m / z 400 (M + H), 417 ( _{+ NH 4), 422 (M} + Na).

44g. 3-((4S) -4- {1-Methyl-1-[(2,4,6-trimethoxyphenyl) methylthio] ethyl} -2-oxo-1,3-oxazolidine-3-yl) propyl (2S ) -2- (6-Methoxy (2-naphthyl)) propanoate DCC (0.39 g, 1.9 mmol) in CH ₂ Cl ₂ (3 ml) was replaced with the product of Example 44f (0.64 g, 1.60 mmol). ), (S) -6-methoxy-α-methyl-2-naphthaleneacetic acid (0.37 g, 1.6 mmol) and DMAP (80 mg, 0.7 mmol) in CH ₂ Cl ₂ (10 ml) at 0 ° C. And added dropwise. The resulting suspension was stirred at 0 ° C. for 1 hour and then at room temperature for 16 hours. The precipitated DCU was removed by filtration and washed with CH ₂ Cl ₂ (10 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was chromatographed on silica gel eluting with 2%, 5% to 10% EtOAc: CH ₂ Cl ₂ to give 0.75 g (77%) of the title compound as a white foam. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.66-7.71 (multit, 3H), 7.39-7.42 (multit, 1H), 7.08-7.14 (m, 2H), 6. 09 (s, 2H), 4.27 to 4.32 (multit, 1H), 4.02 to 4.15 (multit, 3H), 3.89 (s, 3H), 3.80 (s, 3H) 3.78 (s, 6H), 3.70 to 3.91 (multit, 2H), 3.64 to 3.65 (d, J = 1.9 Hz, 2H), 3.54 to 3.62 ( multit, 1H), 3.26 to 3.36 (multit, 1H), 1.83 to 2.03 (multit, 2H), 1.58 (d, J = 7.2 Hz, 3H), 1.33 ( s, 3H), 1.19 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.7, 160.8, 15 9.4, 158.7, 157.8, 135.7, 133.9, 129.4, 129.1, 127.3, 126.3, 126.1, 119.2, 106.8, 105. 7, 90.8, 65.6, 62.2, 61.6, 55.9, 55.5, 55.4, 48.0, 45.6, 42.2, 26.5, 25.8, 22.7,20.5,18.6; mass spectrum (API-TIS) m / z 612 (M + H), 629 (M + NH 4).

44h. 3-[(4S) -4- (1-Methyl-1-sulfanylethyl) -2-oxo-1,3-oxazolidin-3-yl] propyl (2S) -2- (6-methoxy (2-naphthyl) ) Propanoate A mixture of 44 g of the product (0.75 g, 1.2 mmol) was treated with water (490 μl), phenol (490 mg), anisole (490 μl) and finally trifluoroacetic acid (6.0 ml). The solution was stirred at room temperature for 1 hour and evaporated in vacuo to give a yellow oil. This yellow oil was dissolved in CH ₂ Cl ₂ and chromatographed on silica gel eluting with 1: 9, 2: 8 to 1: 2 EtOAc: hexanes to give 0.44 g (83%) of the title compound in white. Obtained as needles. Melting point 118 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.66-7.72 (multit, 3H), 7.39-7.42 (multit, 1H), 7.11-7.17 (m, 2H), 4. 05 to 4.21 (multit, 4H), 3.92 (s, 3H), 3.86 (quart, J = 3.1, 7.2 Hz, 1H), 3.48 to 3.58 (multit, 1H) ), 3.32 to 3.36 (multit, 1H), 3.19 to 3.22 (multit, 1H), 1.82 to 2.09 (multit, 2H), 1.58 (d, J = 7) .2 Hz, 3H), 1.45 (s, 1H), 1.18 (s, 3H), 1.13 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.7, 159.0, 157.9, 135.9, 133.9, 129.4, 129.0, 127.4, 126. 3, 126.0, 119.3, 105.8, 65.6, 65.4, 61.8, 55.5, 47.2, 45.6, 42.5, 28.9, 27.2, 26.4, 18.6; mass spectrum (API-TIS) m / z 432 (M + H), 449 (M + NH ₄ ). Calcd _{(as C 23 H 29 NO 5 S)} : C, 64.01; H, 6.77; N, 3.25; S, 7.43. Experimental: C, 63.95; H, 6.81; N, 3.07; S, 7.26.

44i. 3-{(4S) -4- [1-Methyl-1- (nitrosothio) ethyl] -2-oxo-1,3-oxazolidin-3-yl} propyl (2S) -2- (6-methoxy (2- Naphthyl)) propanoate tert-butyl nitrite (0.17 ml, 0.15 g, 1.48 mmol) in CH ₂ Cl ₂ (3 ml) in a solution of Example 44 g of product (0.32 g, 0.74 mmol) in CH ₂ Cl ₂ solution was added dropwise at 0 ° C. The resulting green solution was stirred in the dark at 0 ° C. for 10 minutes and at room temperature for 20 minutes. The residue after evaporation of the solvent was chromatographed on silica gel eluting with 1: 4 to 1: 2 EtOAc: hexanes to give 0.26 g (76%) of the title compound as a green solid. Mp 116-117 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.66-7.71 (multit, 3H), 7.38-7.42 (multit, 1H), 7.09-7.16 (m, 2H), 4. 28 (s, 3H), 4.05 to 4.18 (multit, 2H), 3.92 (s, 3H), 3.87 (quart, J = 2.9, 7.1 Hz, 1H); 55 to 3.64 (multit, 1H), 3.09 to 3.19 (multit, 1H), 1.72 to 2.02 (multit, 2H), 1.77 (s, 3H), 1.72 ( s, 3H), 1.58 (d, J = 7.2 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 174.7, 158.8, 157.9, 135.7, 133.9, 129 .4, 129.1, 127.4, 126.3, 126.0, 119.2, 105.7 65.1, 63.2, 61.7, 58.9, 55.4, 45.5, 42.5, 26.3, 25.2, 24.6, 18.6; mass spectrum (API- TIS) m / z 461 (M + H), 478 (M + NH 4). Calcd _{(as C 23 H 28 N 2 O 6} S): C, 59.98; H, 6.13; N, 6.08; S, 6.96. Experimental: C, 59.95; H, 6.08; N, 5.89; S, 6.89.

Example 45: {Ethoxy [3-methyl-3- (nitrosothio) butoxy] phosphonyl} methyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate 45a. (Diethoxyphosphoryl) methyl (2S) -2- [6-methoxy (2-naphthyl)] propanoate (2S) -2- (6-methoxy (2-naphthyl) propanoic acid (4.8 g, 20.85 mmol), Diethyl (hydroxymethyl) phosphonate (3.76 g, 22.36 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (4.29 g, 22.38 mmol) and 4- (dimethylamino) A solution of pyridine (catalytic amount) in CH ₂ Cl ₂ (125 ml) was stirred at room temperature for 2 h The reaction was taken up in 0.3 N HCl (150 ml) and extracted with CH ₂ Cl ₂ (3 × 50 ml). the combined extracts were washed with water (2 × 50ml), dried over _Na 2 SO _4, and evaporated in vacuo. the product was silica gel Subjected to column chromatography, 2: 1 EtOAc:. Eluting hexane to give the title compound as a viscous ^{oil, 5.23g (66%) 1 H} NMR (300MHz, CDCl 3) δ7.70~7 .68 (mult, 3H), 7.43~7.37 (mult, 1H), 7.15~7.09 (mult, 2H), 4.38 (d, J H-P = 8.6Hz, 2H ), 4.05 to 3.85 (multit, 5H), 3.95 (s, 3H), 1.60 (d, J = 7.2 Hz, 3H), 1.25 to 1.1 (multit, 6H) ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 173.5 (d, J _C−P = 7.9 Hz), 157.7, 134.9, 133.7, 129.1, 128.8, 127.1 , 126.1, 119.0, 105.5, 62. _{71,62.62,62.61,62.52,57.1 (d, J C-P} = 167.0Hz), 55.2,45.1,18.3,16.20,16.18, 16.12, 16.11; Mass spectrum (API-TIS) m / z 381 (M + H) Elemental analysis: Calculated (as C ₁₉ H ₂₅ O ₆ P): C, 60.0; H, 6.62 Experimental value: C, 59.83; H, 6.41.

45b. (Ethoxy (hydroxyphosphoryl)) methyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate The product of Example 45a (3.25 g, 9.22 mmol) and LiCl (1.0 g, 23.6 mmol). ) In anhydrous DMF (80 ml) was heated at 80 ° C. under argon for 24 hours. DMF was removed under vacuum. The resulting viscous oil was dissolved in methanol (100 ml) and treated with DOWEX-50W-H ⁺ resin (10 g). The mixture was stirred at room temperature for 1.5 hours. The resin was removed by filtration and the filtrate was concentrated. The residue was dissolved in EtOAc (200 ml). The solution was washed with water (3 × 50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was dried under vacuum to give the title compound as a clear oil, 2.61 g (80%). ¹ H NMR (300 MHz, CD ₃ OD) δ 7.74-7.70 (multit, 3H), 7.41-7.38 (multit, 1H), 7.20-7.09 (multit, 2H), 4 _{.36 (d, J H-P} = 8.6Hz, 2H), 4.0~3.78 (mult, 5H), 3.89 (s, 3H), 1.57 (d, J = 7.1Hz , 3H), 1.05 (t, J = 7.1 Hz, 3H); ¹³ C NMR (75 MHz, CD ₃ OD) δ 175.0 (d, J _C−P = 7.6 Hz), 159.0, 136 .4, 135.1, 130.2, 130.0, 128.1, 126.9, 119.8, 106.4, 63.3 (d, J _C−P = 6.1 Hz), 58.4 _{(d, J C-P =} 164.9Hz), 55.5,46.1,18.7,16.4 (d, J C-P = .0Hz); mass spectrum (API-TIS) m / z 351.2 (M-H).

45c. (Ethoxy {3-methyl-3-[(2,4,6-trimethoxyphenyl) methylthio] butoxy} phosphoryl) methyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate Formation of Example 45b Product (1.6417 g, 4.66 mmol), benzotriazol-1-yloxytris- (dimethylamino) phosphonium hexafluorophosphate (3.1168 g, 7.05 mmol) and diisopropylethylamine (3.2 ml, 18.37 mmol). The mixture in anhydrous DMF (40 ml) was stirred at room temperature for 10 minutes. To the resulting brown solution was added 3-methyl-3-[(2,4,6-trimethoxyphenyl) methylthio] butan-1-ol (2.02 g, 6.73 mmol) and 4- (dimethylamino) -pyridine. (0.26 g, 2.13 mmol) was added. After 5.5 hours, DMF was distilled off under reduced pressure. The resulting brown oil was taken up in EtOAc (100 ml). The solution was washed with 1N HCl (2 × 75 ml), water (2 × 75 ml), brine (75 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The product was purified by silica gel column chromatography eluting with 2: 1 EtOAc: hexanes to give the title compound as a viscous oil, 2.08 g (70%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.87-7.83 (multit, 3H), 7.40-7.37 (multit, 1H), 7.14-7.07 (multit, 2H), 6. 09 (s, 2H), 4.40 to 4.37 (multit, 2H), 4.35 to 4.10 (multit, 2H), 3.98 to 3.90 (multit, 3H), 3.89 ( s, 3H), 3.80 (s, 6H), 3.78 (s, 3H), 3.66 (s, 2H), 1.9 to 1.86 (multit, 2H), 1.59 (d , J = 7.2 Hz), 1.28 (s, 3H), 1.27 (s, 3H), 1.17 to 1.11 (multit, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ173. _{4 (d, J C-P} = 7.7Hz), 160.2,158.5,157.5,134.7,13 .6, 129.0, 128.7, 127.0, 125.95, 125.93, 125.9, 125.88, 118.9, 106.8, 105.4, 90.5, 64.19 64.12, 64.05, 60.1, 57.96, 57.89, 55.73, 55.67, 55.6, 55.09, 55.04, 44.9, 43.7, 41 3, 41.2, 28.9, 20.2, 18.2, 16.1, 16.0; mass spectrum (API-TIS) m / z 652 (M + NH ₄ ).

45d. [Ethoxy (3-methyl-3-sulfanylbutoxy) phosphonyl] methyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate Trifluoroacetic acid (10 ml) was obtained as the product of Example 45c (1.04 g , 1.64 mmol) and L-cysteine (2.0 g, 16.5 mmol) and stirred at room temperature for 45 minutes. TFA was distilled off under reduced pressure. The residue was taken up in EtOAc (125 ml). The solution was washed with water (5 × 125ml), dried over _Na 2 SO _4, and concentrated under reduced pressure. The product was purified by silica gel column chromatography eluting with 3: 2 EtOAc: hexanes to give the title compound as a viscous oil, 0.61 g (82%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.7 to 7.67 (multit, 3H), 7.40 to 7.37 (multit, 1H), 7.14 to 7.07 (multit, 2H), 4. 43 to 4.38 (multit, 2H), 4.2 to 3.85 (multit, 5H), 3.87 (s, 3H), 1.8 to 1.7 (multit, 2H), 1.65 1.55 (multit, 4H), 1.28 (s, 3H), 1.27 (s, 3H), 1.2 to 1.05 (multit, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ173 _{.2 (d, J C-P} = 7.0Hz), 157.5,134.7,134.6,133.5,129.0,128.6,126.9,125.9,125.8 , 118.8, 105.3, 63.8, 63.7, 63.6, 62.7, 62.6 62.5, 57.8, 55.5, 55.0, 45.7, 45.6, 44.84, 44.80, 42.3, 32.6, 18.15, 18.07, 16. 02, 15.95; mass spectrum (API-TIS) m / z 455 (M + H).

45e. {Ethoxy [3-methyl-3- (nitrosothio) butoxy] phosphonyl} methyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate tert-butyl nitrite (0.45 ml, 3.4 mmol) To the solution of the product of Example 45d in CH ₂ Cl ₂ (20 ml) and stirred for 2 hours at room temperature in the dark under argon. The resulting green solution was concentrated to dryness under reduced pressure. The product was purified by silica gel column chromatography eluting with 5: 4 EtOAc: hexanes to give the title compound as an oil, 237 mg (44%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.68-7.65 (multit, 3H), 7.40-7.36 (multit, 1H), 7.14-7.07 (multit, 2H), 4. 44 to 4.36 (multit, 2H), 4.2 to 3.85 (multit, 5H), 3.87 (s, 3H), 2.37 to 2.33 (multit, 2H), 1.76 ( s, 3H), 1.74 (s, 3H), 1.6 to 1.57 (multit, 3H), 1.2 to 1.12 (multit, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ173 _{.2 (d, J C-P} = 7.0Hz), 157.5,134.7,134.6,133.5,129.0,128.6,126.9,125.9,125.8 , 118.8, 105.3, 63.8, 63.7, 63.6, 62.7, 62 6, 62.5, 57.8, 55.5, 55.0, 45.7, 45.6, 44.84, 44.80, 42.3, 32.6, 18.15, 18.07, 16.02, 15.95; mass spectrum (API-TIS) m / z 455 (M + H).

Example 46: 6- (4-{[2-Methyl-2- (nitrosothio) propyl] amino} pyrimidin-2-ylthio) hexyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate 46a. 4-Chloro-2- (methylsulfonyl) pyrimidine m-chloroperoxybenzoic acid (57-86%, 24.24 g, 80-121 mmol) was replaced with 4-chloro-2-methylthiopyrimidine (6.41 g, 39.9 mmol). Of CH ₂ Cl ₂ (120 ml) was added to an ice-cold solution. The reaction was stirred in an ice bath for 10 minutes and at room temperature for 3 hours. The reaction was quenched with 6% Na ₂ S ₂ O ₃ (50 ml). Saturated NaHCO ₃ (100 ml) was carefully added to the resulting mixture. The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 50 ml). The combined organic extracts were washed with saturated NaHCO ₃ (50 ml), water, brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was dissolved in CH ₂ Cl ₂ (20 ml) and triturated with hexane (ca. 120 ml) to precipitate the title compound. The white solid was collected on a sintered glass funnel and washed with hexane (50 ml). The filtrate was concentrated and the residue was processed as described above to give a second crop. The solid was dried under vacuum to give the title compound as a white powder, 5.8 g (86%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.87 (d, J = 5.4 Hz, 1H), 7.56 (d, J = 5.4 Hz, 1H), 3.39 (s, 3H); ¹³ C _{NMR (75MHz, CDCl 3) δ166.1,163.3,159.4,124.7,97.15,39.1} ; mass spectrum (API-TIS) m / z 193 (M + H). Calcd _{(as C 5 H 5 ClN 2 O 2} S): C, 31.18; H, 2.62; N, 14.54. Experimental value: C, 31.21; H, 2.63; N, 14.55.

46b. 6- (4-Chloropyrimidin-2-ylthio) hexane-1-ol 6-mercapto-1-hexanol (1.4 ml, 10.2 mmol) was added to NaH (60% in mineral oil, 0.42 g, 10.5 mmol). To a suspension in THF (20 ml) and stirred at room temperature for 10 minutes, then cooled to −78 ° C. in a dry ice bath. A suspension of the product of Example 46a (1.74 g, 9.03 mmol) was added to the above mixture and stirred at −78 ° C. for 2.5 hours. The reaction was quenched with water (20 ml) and extracted with Et ₂ O (100 ml). The extract was washed with water (2 × 100 ml) and brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography eluting with 1: 2 EtOAc: hexanes to give the title compound as a viscous oil, 1.8 g (81%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.67 (d, J = 5.3 Hz, 1H), 7.00 (d, J = 5.3 Hz, 1H), 3.63 (t, J = 6.6 Hz) , 2H), 3.14 (t, J = 7.4 Hz, 2H), 2.60 (s, 1H), 1.8 to 1.4 (multit, 8H); ¹³ C NMR (75 MHz, CDCl ₃ ). δ 173.4, 160.7, 157.8, 116.2, 62.3, 32.3, 30.8, 28.6, 28.3, 25.1; mass spectrum (API-TIS) m / z 247 (M + H).

46c. 1-amino-2-methylpropane-2-thiol To a suspension of 2-mercapto-2-methyl-1-propylamine hydrochloride (8 g, 56.7 mmol) in absolute Et ₂ O (100 ml) was added triethylamine (20 ml, 143.5 mmol) was added. The reaction mixture was stirred at room temperature overnight and filtered. The filtrate was evaporated to give the title compound as a volatile solid (3.95 g, 91%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.77 (s, 2H), 1.72 (s, 3H), 1.34 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 56.2, 46 .9, 29.6.

46d. 6- {4-[(2-Methyl-2-sulfanylpropyl) amino] pyrimidin-2-ylthio} hexane-1-ol The product of Example 46b (1.65 g, 6.69 mmol) and the formation of Example 46c A solution of the product (1.91 g, 18.2 mmol) in anhydrous pyridine (40 ml) was degassed with two freeze-pump-thaw cycles and covered with argon. The reaction was heated to 70 ° C. overnight and then pyridine was distilled off. The residue was chromatographed on silica gel eluting with 1: 1 EtOAc: hexane to give 0.57 g (27%) of the title compound. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.91 (d, J = 5.8 Hz, 1H), 6.06 (d, J = 5.8 Hz, 1H), 5.78 (br, 1H), 3. 63 (t, J = 6.6 Hz, 2H), 3.50 (br, 2H), 3.06 (t, J = 7.4 Hz, 2H), 2.94 (s, 1H), 1.79 ( s, 1H), 1.8-1.2 (multit, 8H), 1.38 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.9, 161.8, 154.8, 100. 0, 62.2, 53.3, 45.4, 32.4, 30.3, 29.9, 29.3, 28.5, 25.2; mass spectrum (API-TIS) m / z 316 ( M + H).

46e. 6- (4-{[2-Methyl-2- (nitrosothio) propyl] amino} pyrimidin-2-ylthio) hexane-1-ol tert-butyl nitrite (90%, 0.3 ml, 2.27 mmol). To the solution of the product of Example 46d (0.55 g, 1.74 mmol) in CH ₂ Cl ₂ (25 ml) and HCl (1N, 2 ml). The mixture was stirred in the dark at room temperature for 3 hours. The reaction mixture was partitioned and basified with saturated NaHCO ₃ (20 ml) and water (20 ml). The aqueous layer was separated and extracted with CH ₂ Cl ₂ (2 × 30 ml). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by silica gel column chromatography eluting with 3: 2 EtOAc: hexanes to give the title compound as a green oil, 0.43 g (71%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (d, J = 5.9 Hz, 1H), 5.95 (d, J = 5.9 Hz, 1H), 5.10 (br, 1H), 4. 21 (br, 2H), 3.65 (t, J = 6.5 Hz, 2H), 3.09 (t, J = 7.4 Hz, 2H), 1.92 (s, 6H), 1.8- 1.4 (multit, 8H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 171.0, 161.9, 154.8, 100.6, 62.3, 57.3, 50.4, 32.4, 30.4, 29.3, 28.6, 26.7, 25.2; mass spectrum (API-TIS) m / z 345 (M + H).

46f. 6- (4-{[2-Methyl-2- (nitrosothio) propyl] amino} pyrimidin-2-ylthio) hexyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate Product of Example 46e (0.355 g, 1.03 g), (2S) -2- (6-methoxy (2-naphthyl)) propanoic acid (0.2517 g, 1.09 mmol), 1- [3- (dimethylamino) propyl]- A solution of 3-ethylcarbodiimide hydrochloride (0.2411 g, 1.26 mmol) and 4- (dimethylamino) -pyridine (5 mg) in CH ₂ Cl ₂ (25 ml) was stirred at room temperature for 2.5 hours. The reaction was washed with water (50 ml) and saturated NaHCO ₃ (1 ml). These aqueous washes were back extracted with _{CH 2 Cl 2 (2 × 30ml} ). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by silica gel column chromatography eluting with 3: 5 EtOAc: hexanes to give the title compound as a green oil, 0.46 g (76%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.87 (d, J = 5.9 Hz, 1H), 7.69-7.65 (multit, 3H), 7.41-7.37 (multit, 1H), 7.13 to 7.09 (multit, 2H), 5.99 (d, J = 5.9 Hz, 1H), 5.64 (br, 1H), 4.15 (br, 2H), 4.06 ( t, J = 6.6 Hz, 2H), 3.88 to 3.83 (multit, 1H), 3.86 (s, 3H), 2.97 (t, J = 7.4 Hz, 2H), 1. 85 (s, 6H), 1.65 to 1.53 (multit, 7H), 1.37 to 1.24 (multit, 4H); mass spectrum (API-TIS) m / z 557.0 (M + H). Calcd _{(as C 28 H 36 N 4 O 4} S 2): C, 60.41; H, 6.52; N, 10.06. Experimental value: C, 60.14; H, 6.37; N, 9.78.

Example 47: {(2S, 5S) -5- [1-methyl-1- (nitrosothio) ethyl] -3,6-dioxopiperazin-2-yl} methyl (2S) -2- (6-methoxy ( 2-naphthyl)) propanoate 47a. (2S) -2-Amino-3-[(4-methoxyphenyl) methylthio] -3-methylbutanoic acid (2S) -amino-3-methyl-3-sulfanylbutanoic acid (11.5 g, 77.2 mmol) in CH _The suspension in 2Cl ₂ (60 ml) was treated with trifluoroacetic acid (13.7 ml) and dissolved by stirring at room temperature. The mixture was then cooled to −10 ° C. under nitrogen. A solution of 4-methoxybenzyl chloride (10.5 ml, 77.25 mmol) in CH ₂ Cl ₂ (90 ml) was added dropwise from another funnel over 1.5 hours. Stirring was continued for 1.5 hours at room temperature. Methanol (10 ml) was added to dissolve the precipitate. The crude reaction was concentrated under vacuum. The residue was dissolved in CH ₂ Cl ₂ (40 ml) and extracted with water (7 × 50 ml). The combined aqueous extracts were frozen and lyophilized. The residue was dissolved in methanol / water (1: 3, 200 ml) and the pH was adjusted to 6-7 using sodium bicarbonate. A white solid was isolated by filtration, rinsed with MeOH / water (1: 3) and dried to give the title compound (6.92 g, 33%). ¹ H NMR (300 MHz, CD ₃ OD) δ 7.28 (d, J = 7.0 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 3.79-3.76 (m, 5H), 3.51 (s, 1H), 1.63 (s, 3H), 1.33 (s, 3H).

47b. (4S) -4- {1-[(4-Methoxyphenyl) methylthio] -isopropyl} -1,3-oxazolidine-2,5-dione The product of Example 47a (3.0 g, 11.1 mmol) was nitrogenated. Suspended in THF (45 ml) at 0 ° C. A solution of phosgene (17 ml, 33.4 mmol) was added slowly. The solution was stirred at 0 ° C. for 30 minutes and then warmed to room temperature for 22 hours. The solvent was removed under vacuum. The yellowish oil was dried overnight under high vacuum without further purification. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.31 (d, J = 9.0 Hz, 2H), 7.16 (d, J = 8.9 Hz, 2H), 4.39 (s, 1H), 3 .82~3.73 (m, 5H), 1.51 (s, 3H), 1.35 (s, 3H); mass spectrum (API-TIS) m / z 313 (M + NH 4).

47c. Methyl (2S) -2-{(2S) -2-amino-3-[(4-methoxyphenyl) methylthio] -3-methylbutanoylamino} -3-hydroxypropanoate Methyl at -78 ° C under nitrogen ( To a stirred suspension of 2S) -2-amino-3-hydroxypropanoate hydrochloride (1.73 g, 11.1 mmol) in CHCl ₃ (50 ml) was added triethylamine (3.9 ml, 27.8 mmol) and the examples. A solution of the product of 47b in THF (30 ml) was added. The resulting solution was stirred at −78 ° C. for 4 hours and then warmed to room temperature overnight. The solvent was removed under vacuum. The residue was partitioned between Et ₂ O and H ₂ O. The organic phase was washed with brine, dried over MgSO ₄ , filtered and concentrated to give the title compound (3.17 g), which was used in the next step without further purification. Mass spectrum (API-TIS) m / z 371 (M + H).

47d. (3S, 6S) -3- (Hydroxymethyl) -6- {1-[(4-methoxyphenyl) methylthio] -isopropyl} piperazine-2,5-dione The product of Example 47c in toluene (50 ml) Refluxed for 24 hours, gradually cooled to room temperature, and stored at -4 ° C for 24 hours. The solid was isolated by filtration, rinsed with ether and dried to give the title compound (0.8 g, 47b to 21%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.19 (br, 1H), 8.02 (br, 1H), 7.25 (d, J = 8.57 Hz, 2H), 6.89 (d, J = 8.59 Hz, 2H), 4.92 to 4.84 (m, 1H), 4.08 to 4.06 (m, 1H), 3.81 to 3.76 (m, 5H), 1.49 ( s, 3H), 1.44 (s, 3H); mass spectrum (API-TIS) m / z 339.0 (M + H).

47e. ((2S, 5S) -5- {1-[(4-methoxyphenyl) methylthio] -isopropyl} -3,6-dioxopiperazin-2-yl) methyl (2S) -2- (6-methoxy (2 -Naphthyl)) propanoate The product of Example 47d (620 mg, 1.8 mmol), (2S) -2- (6-methoxy (2-naphthyl)) propanoic acid (421 mg, 1.8 mmol), 4- (dimethylamino) A mixture of) -pyridine (223 mg, 1.8 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (421 mg, 2.20 mmol) in DMF (25 ml) was stirred overnight at room temperature under nitrogen. The precipitate was removed by filtration and the mother liquor was triturated with Et ₂ O: CH ₂ Cl ₂ (1: 1, 10 ml). The precipitated solid was isolated by filtration, rinsed with Et ₂ O and dried to give the title compound (0.46 g, 46%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.36-8.39 (m, 2H), 7.72-7.83 (m, 3H), 7.15-7.42 (m, 5H), 6.83 to 6.88 (d, 2H), 4.41 to 4.45 (m, 2H), 4.28 (d, J = 9.6 Hz, 1H), 3.87 to 3.97 (m) , 4H), 3.66 to 3.77 (m, 5H), 3.56 to 3.57 (m, 1H), 1.48 (d, J = 7.0 Hz, 3H), 1.41 (s) , 3H), 1.35 (s, 3H); mass spectrum (API-TIS) m / z 551.0 (M + H).

47f. [(2S, 5S) -5- (1-Methyl-1-sulfanylethyl) -3,6-dioxopiperazin-2-yl] methyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate A solution of the product of Example 47e (450 mg, 0.82 mmol), anisole (0.61 ml, 5.50 mmol), trifluoroacetic acid (0.32 ml) in CH ₂ Cl ₂ (1.5 ml) was cooled to 0 ° C. And trifluoromethanesulfonic acid (0.6 ml) was added dropwise. The resulting solution was stirred at 0 ° C. for 30 minutes and then at room temperature for 2 hours. The mixture was diluted with Et ₂ O (5 ml) and H ₂ O (5 ml). The precipitated solid was isolated by filtration, rinsed with Et ₂ O and dried to give the title compound (160 mg, 45%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.48 (br, 1H), 8.29 (br, 1H), 7.72-7.83 (m, 3H), 7.16-7.42 ( m, 3H), 4.40 to 4.44 (m, 2H), 4.22 to 4.24 (m, 1H), 3.88 to 3.94 (m, 4H), 3.56 (br, 1H), 2.72 (s, 1H), 1.36 to 1.49 (m, 9H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 173.6, 165.7, 165.4, 157. 3, 135.3, 133.3, 129.2, 128.4, 126.9, 126.3, 125.6, 118.7, 105.7, 64.8, 64.6, 55.2, 53.3, 49.6, 44.3, 30.5, 29.7, 18.5; mass spectrum (API-TIS) m / z 4 1 (M + H).

47g. {(2S, 5S) -5- [1-Methyl-1- (nitrosothio) ethyl] -3,6-dioxopiperazin-2-yl} methyl (2S) -2- (6-methoxy (2-naphthyl) ) Propanoate The product of Example 47f (150 mg, 0.35 mmol) was dissolved in DMF (25 ml) by sonication. To this solution, tert-butyl nitrite (0.14 ml, 1.05 mmol) was added dropwise under nitrogen. The resulting solution was stirred at room temperature for 2 hours. The solvent was removed and the residue was triturated with Et ₂ O. The solid was isolated by filtration and dried to give the title compound (130 mg, 81%). Melting point> 180 ° C. (decomposition); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 8.36 (s, 1H), 7.71 to 7.83 (m, 3H), 7.15-7.40 (m, 3H), 3.88-4.38 (m, 8H), 2.03 (s, 3H), 1.98 (s, 3H), 1.46 (d, J = 6.8 Hz, 3H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 173.5, 165.4, 164.5, 157.2, 135.3, 133.3, 129.2, 128. 3, 126.9, 126.3, 125.6, 118.7, 105.7, 63.8, 63.2, 61.9, 55.1, 53.0, 44.3, 26.6, 25.9,18.5; mass spectrum (API-TIS) m / z 477 (M + NH 4).

Example 48: 2- (N-methyl {1- [2-methyl-2- (nitrosothio) propyl] (4-piperidyl)} carbonylamino) ethyl (2S) -2- (6-methoxy (2-naphthyl) ) Propanoate 48a. Ethyl 1- (2-methyl-2-sulfanylpropyl) piperidine-4-carboxylate Ethyl piperidine-4-carboxylate (3.6 g, 22.9 mmol) is dissolved in benzene (5 ml) and 2,2- Dimethyl thiirane (5.04 g, 57.3 mmol) was added. The reaction mixture was stirred at 80 ° C. for 20 hours, poured into water and extracted several times with EtOAc. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. Volatiles were removed and the residue was dried under vacuum to give 5.45 g (97%) of the title compound. ¹ H NMR (300 MHz, CD ₃ OD) δ 4.12 (q, J = 7.1 Hz, 2H), 2.92-2.96 (d, J = 11.9 Hz, 2H), 2.19-2. 40 (m, 6H), 1.61-1.86 (m, 4H), 1.29 (s, 6H), 1.25 (t, J = 7.1 Hz, 2H).

48b. 1- (2-Methyl-2-sulfanylpropyl) piperidine-4-carboxylic acid The product of Example 48a (5.3 g, 21.6 mmol) was dissolved in ethanol (25 ml) and sodium hydroxide (3. 1 g, 77.9 mmol) in water (30 ml) was added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and concentrated HCl was added to pH 5.6. Ethanol was added and volatiles were distilled off. The residue was suspended in EtOAc and filtered. The filter cake was washed with CH ₂ Cl ₂ and the filtrate was concentrated in vacuo to give 4.5 g (96%) of the title compound. ¹ H NMR (300 MHz, CD ₃ OD) δ 3.13 (d, 2H), 2.55 to 2.68 (m, 4H), 2.17 to 2.26 (9 m, 1H), 1.77 to 1 .92 (m, 5H), 1.32 (s, 6H).

48c. 1- [2-Methyl-2- (nitrosothio) propyl] piperidine-4-carboxylic acid The product of Example 48b (1.31 g, 6.04 mmol) was dissolved in anhydrous methanol (20 ml) and 2N HCl ( 12 ml, 24 mmol) was added. The resulting mixture was cooled to 0 ° C. and a solution of sodium nitrite (1.66 g, 24.1 mmol) in water (5 ml) was added. The reaction mixture was stirred at 0 ° C. for 40 minutes. Ethanol (30 ml) was added and volatiles were distilled off. The residue was dissolved in ethanol and filtered to remove sodium chloride. The filtrate was concentrated in vacuo and the residue was subjected to silica gel flash chromatography, eluting with 100: 1 to 40: 1 CH ₂ Cl ₂ : MeOH to purify 0.73 g (49%) of the title compound as a green oil. Got as. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.04 (s, 2H), 2.87-2.93 (m, 2H), 2.46 (t, 2H), 2.30-2.34 (m, 1H), 1.89 (s, 6H), 1.68-1.87 (m, 4H).

48d. (Tert-Butoxy) -N- (2-hydroxyethyl) -N-methylcarboxamide N-methylaminoethanol (5.1 g, 67.7 mmol) was dissolved in THF (70 ml) and di-tert-butyl di- Carbonate (15.7 g, 72 mmol) was added. The resulting solution was stirred at room temperature for 18 hours. Volatiles were removed and the residue was dried overnight under vacuum to give 11.2 g (95%) of the title compound. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.74 (t, 2H), 3.38 (t, 2H), 2.91 (s, 3H), 2.21 (s, 1H), 1.46 (s , 9H).

48e. 2-[(tert-Butoxy) -N-methylcarbonylamino] ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate Under a nitrogen atmosphere, (2S) -2- (6-methoxy (2 - naphthyl)) propanoic acid (5.0 g, 21.7 mmol) was dissolved in anhydrous _CH 2 _Cl 2 (50ml), and 4-dimethylaminopyridine (2.65 g, 21.7 mmol) was added. The product of Example 48d (3.8 g, 21.7 mmol) was then added followed by a solution of 1,3-dicyclohexylcarbodiimide (4.1 g, 21.7 mmol) in CH ₂ Cl ₂ (50 ml). The resulting mixture was stirred at room temperature for 18 hours. The solvent was removed and the residue was purified by flash chromatography on silica gel eluting with 9: 1 hexane: EtOAc to give 6.04 g (72%) of the title compound. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.68 (t, 3H), 7.39 (d, 1H), 7.10 to 7.18 (m, 2H), 4.12 to 4.20 (m, 2H), 3.91 (s, 3H), 3.86 (q, 1H), 3.34 to 3.40 (m, 2H), 2.71 (s, 3H), 1.57 (d, 3H) ), 1.43 (s, 9H).

48f. 2- (Methylamino) ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate The product of Example 48e (6.04 g, 15.6 mmol) was dissolved in CH ₂ Cl ₂ (50 ml). And anisole (1.7 ml, 15.6 mmol) was added followed by TFA (50 ml). The resulting mixture was stirred at room temperature for 15 minutes. Toluene was added and volatiles were distilled off. The residue was purified by silica gel flash chromatography eluting with 30: 1 CH ₂ Cl ₂ : MeOH to give 3.0 g (68%) of the title compound as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.60-7.73 (m, 3H), 7.33-7.38 (m, 1H), 7.10-7.17 (m, 2H), 3. 98 (q, 1H), 3.91 (s, 3H), 3.73 to 3.82 (m, 2H), 3.56 (t, 2H), 2.97 (d, 3H), 1.50 (D, 3H).

48g. 2- (N-methyl {1- [2-methyl-2- (nitrosothio) propyl] (4-piperidyl)} carbonylamino) ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate Nitrogen atmosphere Below, the product of Example 48f (0.852 g, 2.98 mmol) was dissolved in CHCl ₃ (20 ml) and the product of Example 48c (0.730 g, 2.98 mmol) was added. The resulting mixture was cooled to 0 ° C., and 4-dimethylaminopyridine (0.145g, 1.19mmol), followed by _CH 2 _Cl 2 (10ml) solution of 1,3-dicyclohexylcarbodiimide (0.614 g, 2 .98 mmol) was added. The resulting mixture was stirred at 0 ° C. for 5 hours. The precipitate was filtered, the filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography eluting with 3: 1 hexane: EtOAc to give 1.1 g (72%) of the title compound as a green foam. Obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.60-7.75 (m, 3H), 7.32-7.38 (m, 1H), 7.07-7.20 (m, 2H), 3. 97 to 4.31 (m, 3H), 3.67 to 3.92 (m, 4H), 3.25 to 3.43 (m, 1H), 2.99 (s, 2H), 2.93 ( s, 2H), 2.85 (s, 1H), 2.72 (d, 1H), 2.60 (d, 1H), 1.84 to 2.21 (m, 3H), 1.81 (s) , 6H), 1.25 to 1.50 (m, 7H).

Example 49: 4-({4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} carbonyl) phenyl 2 {2-[(2,6-dichlorophenyl) amino] phenyl} acetate 49a. 4-Hydroxyphenyl 4- (2-methyl-2-sulfanylpropyl) piperazinyl ketone Solid K ₂ CO ₃ (153 mg, 1.10 mmol) and the product of Example 39b (1.86 g, 5.52 mmol) in MeOH The mixture in (25 ml) was stirred at room temperature for 15 minutes. Inorganic solids were removed by filtration and the filtrate was concentrated. The residue was crystallized from EtOAc to give the title compound (1.50 g, 92%) as a white solid. Melting point 46 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.23 (d, J = 8.5 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H), 4.0 to 3.4 (Br, 4H), 2.8-2.5 (br, 4H), 2.43 (s, 2H), 1.30 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 171.2, 158.7, 128.9, 125.3, 115.3, 70.8, 55.1, 46.0, 30.0.

49b. 4-Hydroxyphenyl 4- [2-methyl-2- (nitrosothio) propyl] piperazinyl ketone To a stirred solution of the product of Example 49a (1.0 g, 3.4 mmol) in MeOH (15 ml) at 0 ° C. 12N HCl (0.29 ml, 3.5 mmol) and t-BuONO (0.51 ml, 4.0 mmol) were added. After 10 minutes, the mixture was partitioned between EtOAc and aqueous Na ₂ CO ₃ . The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (0.95 g, 91%) as a green foam. ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.2 (br, 1H), 7.19 (m, 2H), 6.71 (m, 2H), 3.8 to 3.4 (br, 4H), 3 .03 (s, 2H), 2.7-2.5 (br, 4H), 1.88 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 171.4, 158.8, 129.0 125.5, 115.5, 68.0, 58.5, 55.2, 26.9.

49c. 4-({4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} carbonyl) phenyl 2 {2-[(2,6-dichlorophenyl) amino] phenyl} acetate The product of Example 49b (1.20 g , 3.72mmol), (2 - ( (2,6- dichlorophenyl) amino) benzene) acetate (1.10 g, 3.72 mmol) and DCC (0.770 g, 3.72 mmol) in _CH 2 _Cl 2 (30ml) The medium mixture was stirred at room temperature for 2 hours. The solid that formed was removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel eluting with 2: 1 hexane: EtOAc to give the title compound (2.0 g, 90%) as a green solid. Melting point 61-62 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.4 to 6.4 (m, 12H), 3.96 (s, 2H), 3.8 to 3.3 (multit, 4H), 2.94 (s, 2H), 2.7-2.4 (multit, 4H), 1.79 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.2, 169.3, 151.4, 142.6, 137.6, 133.3, 130.9, 129.4, 128.8, 128.5, 128.3, 124.1, 123.6, 122.3, 121.6, 118.5, 68. 0, 58.4, 55.1, 38.4, 26.9.

Example 50: 3-[(2S) -2- (6-Methoxy (2-naphthyl) propanoyloxy] -2-oxopropyl-3-methyl-3- (nitrosothio) butanoate 50a. 3-Chloro-2- Oxopropyl 3-methyl-3-[(2,4,6-trimethoxyphenyl) methylthio] butanoate 3-methyl-3-[(2,4,6-trimethoxyphenyl) methylthio] butanoic acid (3 g, 9. 54 mmol) and sodium bicarbonate (975 mg, 11.6 mmol) in DMF (30 ml) was added 1.3-dichloroacetone (4.23 g, 33.4 mmol) in DMF (15 ml) at 0 ° C. under nitrogen. was. the reaction mixture was warmed to room temperature and the residue after distillation was stirred for 48 hours. the solvent was partitioned between EtOAc and H _{2 O.} Yes The phases were washed with water and brine, dried over MgSO _4, filtered, and subjected concentrated residue to silica gel chromatography, EtOAc:. Hexane and eluted with (20-30%) the title compound as a yellow oil ( 2.19 g, 57%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.12 (s, 2H), 4.87 (s, 2H), 4.21 (s, 2H), 3.86 ˜3.80 (multit, 11H), 2.83 (s, 2H), 1.52 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 196.5, 170.1, 160.4, 158 .6, 107.3, 90.7, 66.4, 55.8, 55.3, 46.3, 45.9, 43.8, 28.2, 20.9; mass spectrum (API-TIS) _{m / z 422 (M + NH} 4).

50b. 3-[(2S) -2- (6-methoxy (2-naphthyl) propanoyloxy] -2-oxopropyl 3-methyl-3-[(2,4,6-trimethoxyphenyl) methylthio] butanoate (2S ) -2- (6-Methoxy (2-naphthyl)) propanoic acid (1.25 g, 5.41 mmol) and sodium bicarbonate (545 mg, 6.49 mmol) in DMF (15 ml) was added to a stirred mixture of Example 50a. A solution of the product (2.19 g, 5.41 mmol) in DMF (10 ml) was added at room temperature under nitrogen and the reaction mixture was stirred for 4.5 days After evaporation of the solvent, the residue was washed between EtOAc and H ₂ O. The organic phase was washed with brine, dried over MgSO ₄ , filtered, and concentrated The residue was chromatographed on silica gel, CH ₂ Cl ₂ : hexanes. Elution with sun (80% -100%) gave the title compound (700 mg, 21.6%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.70-7.73 (multit, 3H), 7. 41 to 7.44 (multit, 1H), 7.12 to 7.17 (multit, 2H), 6.09 (s, 2H), 4.75 (d, J = 3.8 Hz, 2H). 60 (d, J = 4.3 Hz, 2H), 3.95 to 4.02 (multit, 1H), 3.91 (s, 3H), 3.78 (multit, 11H), 2.78 (s, 2H), 1.64 (d, J = 7.2 Hz, 3H), 1.48 (s, 6H).

50c. 3-[(2S) -2- (6-Methoxy (2-naphthyl) propanoyloxy] -2-oxopropyl-3-methyl-3-sulfanylbutanoate The product of Example 50b (700 mg, 1.17 mmol ), Phenol (132 mg, 1.40 mmol), anisole (0.14 ml, 1.51 mmol), water (0.03 ml) and trifluoroacetic acid (4.2 ml) were stirred at room temperature for 1 hour. The residue was dissolved with EtOAc, the solution was carefully neutralized with NaHCO _{3. The} organic phase was washed with water and brine, dried over MgSO ₄ , filtered and concentrated. the residue was chromatographed on silica gel, 2: 8 ^EtOAc:. elution with hexane to give the title compound (250mg, 51%) 1 H N Rδ 7.69-7.74 (multit, 3H), 7.39-7.43 (multit, 1H), 7.16-7.11 (multit, 2H), 4.73 (d, J = 0.9 Hz) , 2H), 4.62 (d, J = 6.3 Hz, 2H), 3.94 to 4.02 (multit, 1H), 3.91 (s, 3H), 2.70 (s, 2H), 2.32 (s, 1H), 1.63 (d, J = 7.2 Hz, 3H), 1.49 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 197.8, 173.8, 169.7, 157.8, 134.8, 133.8, 129.3, 128.9, 127.3, 126.1, 119.1, 105.7, 66.6, 55.3, 49. 9, 45.0, 41.5, 32.4, 18.4; mass spectrum (API-TIS) m / z 436 (M + H _4).

50d. 3-[(2S) -2- (6-Methoxy (2-naphthyl) propanoyloxy] -2-oxopropyl-3-methyl-3- (nitrosothio) butanoate Product of Example 50c (240 mg, 0.57 mmol ) In CH ₂ Cl ₂ (12 ml) was added tert-butyl nitrite (0.23 ml, 1.72 mmol) at room temperature under nitrogen The mixture was stirred for 1 hour. The residue was chromatographed on silica gel eluting with 2: 8 EtOAc: hexane to give the title compound (160 mg, 63%), mp 45-46 ° C. ¹ H NMR δ 7.69-7.73 (multi) , 3H), 7.39-7.42 (multit, 1H), 7.11-7.16 (multit, 2H), 4.69 (s, 2H), 4.59 ( d, J = 6.9 Hz, 2H), 3.97 to 4.01 (multit, 1H), 3.91 (s, 3H), 3.32 (s, 2H), 1.98 (s, 6H) , 1.63 (d, J = 7.2 Hz, 3H); ¹³ C NMR δ 197.5, 173.7, 169.0, 157.8, 134.8, 133.8, 129.3, 128.9, 127.3, 126.1, 119.1, 105.6, 66.6, 66.1, 55.2, 53.3, 46.6, 45.0, 28.7, 18.3; mass spectrum (API-TIS) m / z 465 (M + NH 4).

Example 51: Comparative in vivo analgesia, anti-inflammatory and gastric lesion activity Analgesic activity was measured using a phenylbenzoquinone-induced distress test in mice. The ability of these compounds to block phenylbenzoquinone-induced distress in mice was measured using the method of Siegmund et al., Proc. Soc. Exp. Biol. Med. 95: 729-731, 1957. Male CD-1 mice (Charles River Laboratories, Wilmington, Mass.) Weighing 20-25 g were fasted overnight. Vehicle or compound was administered by oral tube one hour prior to intraperitoneal injection of phenylbenzoquinone 2 mg / kg. Five minutes after intraperitoneal injection of phenylbenzoquinone, the number of pains in 5 minutes was counted.
Anti-inflammatory activity was measured using the rat paw edema test. The rat paw edema test was performed according to the method of Winter et al., Proc. Soc. Exp. Biol. Med. 111: 544-547, 1962. Male Sprague-Dawley rats (250-275 g) were fasted overnight and vehicle or compound suspensions were administered via oral tube one hour prior to the injection of 50 μl of 1% carrageenan suspension under the sole of the foot. After 3 hours, paw volume was measured and compared to the initial volume measured immediately after carrageenan injection.

Kitagawa et al., J. Pharmacol. Exp. Ther., 253: 1133-1137 (1990) and Al-Ghamdi et al., J. Int. Med. Res., 19: 2242 (1991). The rat gastric lesion test described was used to evaluate the activity of compounds that cause gastric lesions. For these experiments, male Sprague-Dawley rats (Charles River Laboratories, Wilmington, Mass.) Weighing 230-250 g were used. Rats were housed and given laboratory food and water ad libitum prior to testing. Rats were fasted with water ad libitum for 24 hours and then dosed with a vehicle or test compound at a dose volume of 0.5 ml / 100 g by oral tube. Food was discontinued for 18 hours after the first dose. Rats were euthanized with CO ₂ 18 hours after dosing. The stomach was cut along the great bay, flushed with 0.9% saline directly, and opened and pinned on a sylgard petri dish to examine bleeding lesions. The gastric lesion score was expressed in mm and calculated by summing the length of each lesion.
Table 1 shows the relative activity of the compounds in analgesic, anti-inflammatory and gastric lesion studies and these are expressed as the ratio of activity to the parent NSAID. These results indicate that nitrosated NSAIDs have comparable or strong analgesic and anti-inflammatory activity compared to their parent NSAID molecules. Table 1 also shows that the nitrosated NSAIDs of the present invention have significant and unexpectedly low gastric lesion activity.

The disclosures of each patent, patent application and publication cited or described in this specification are hereby incorporated by reference in their entirety.
Although the present invention has been described in detail, those skilled in the art can make numerous changes and modifications to the present invention and such changes and modifications without departing from the spirit and scope of the present invention. It will be understood that modifications can be made.

Claims (39)

A compound represented by the following formula (I), formula (II), formula (III) or formula (IV):
Compound of formula (I):

Where R _g is a hydrogen atom or a lower alkyl group;
R _h is:

n is an integer of 0 or 1;
X is:
_{(I) -T-B l -W} -B t -T-NO s;
_{(Ii) -T-B l -L} y -B x -T-NO s;
_{(Iii) -T-B l -W} -B t -W x -B k -T-NO s;
_{(Iv) -T-B l -} (C (R b) (R c)) p -E x -T-NO s;
_{(V) -T-B l -G} -B t -W z -B k -G x -B r -T-NO s;
_{(Viii) -T-B l -J} -E x -T-NO s; or _{(ix) -T-B l -C} (R e) = N-E z -T-NO s;
here,
s is an integer of 1 or 2;
T is each independently a covalent bond, carbonyl, oxygen, -S- (O) _o -or -N (R _a ) R _i- ;
o is an integer from 0 to 2;
R _a is a lone pair, hydrogen or an alkyl group;
_Ri is hydrogen, alkyl, aryl, alkylcarboxylic acid, arylcarboxylic acid, alkylcarboxylic acid ester, arylcarboxylic acid ester, alkylcarboxamide, arylcarboxamide, alkylaryl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, sulfonamide , Carboxamide, carboxylic acid ester, aminoalkyl, aminoaryl, —CH ₂ —C (TQ) (R _e ) (R _f ), or — (N ₂ O ₂ —) ⁻ · M ⁺ (where M ⁺ is an organic or inorganic cation);
L is independently —C (O) —, —C (S) —, —T—, a heterocyclic ring, an aryl group, an alkenyl group, an alkynyl group, an aryl heterocyclic ring, or — (CH _2). CH ₂ O) _q ;
q is an integer from 1 to 5;
B is independently an alkyl group, an aryl group, or — (C (R _e ) (R _f )) _p —, a heterocyclic ring, an aryl heterocyclic ring, or — (CH ₂ CH ₂ O) _{q each time.} Is;
p is an integer from 1 to 10;
R _e and R _f are each independently hydrogen, alkyl, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, aryl heterocyclic ring, alkylaryl, cycloalkylalkyl, heterocyclic alkyl, alkoxy, haloalkoxy , Amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, haloalkoxy, sulfonic acid, alkylsulfonic acid, arylsulfonic acid, arylalkoxy, alkylthio, arylthio, cyano, aminoalkyl, aminoaryl , Alkoxy, aryl, arylalkyl, alkylaryl, carboxamide, alkylcarboxamide, arylcarboxamide, amino , Carboxyl, carbamoyl, alkyl carboxylic acid, aryl carboxylic acid, ester, carboxylic acid ester, alkyl carboxylic acid ester, aryl carboxylic acid ester, haloalkoxy, sulfonamide, alkyl sulfonamide, aryl sulfonamide, urea, nitro, -T -NO _s , or [C (R _e ) (R _f )] _k -T-NO _s , or R _e and R _f are bonded together to form a heterocyclic ring, a cycloalkyl group or a bridge A cycloalkyl group having a bond;
R _b and R _c are each independently haloalkyl, alkenyl group, alkynyl group, cycloalkyl group having a bridge bond, heterocyclic ring, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, aryl heterocyclic ring , Alkylaryl, cycloalkylalkyl, heterocyclic alkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, haloalkoxy, sulfonic acid, alkylsulfonic acid, aryl Sulfonic acid, arylalkoxy, alkylthio, arylthio, cyano, aminoalkyl, aminoaryl, alkoxy, arylalkyl, alkylaryl, cation Boxamide, alkylcarboxamide, arylcarboxamide, amidyl, carboxyl, carbamoyl, alkylcarboxylic acid, arylcarboxylic acid, ester, carboxylic acid ester, alkylcarboxylic acid ester, arylcarboxylic acid ester, haloalkoxy, sulfonamide, alkylsulfonamide, arylsulfone Amide, urea, nitro, -T-NO _s , or (C (R _e ) (R _f )) _k -T-NO _s , or R _b and R _c are bonded together to form carbonyl, methanethiol A heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group;
G is a covalent bond, -TC (O)-, -C (O) -T- or T;
J is carbonyl, phosphoryl or silyl;
k, l, t and z are each independently an integer of 1 to 3;
y is an integer from 1 to 3;
x and r are each independently an integer from 0 to 3;
E is independently —C (O) —, —C (S) —, —T—, — (C (R _e ) (R _f )) _p —, an alkyl group, an aryl group, a heterocyclic ring. , aryl heterocyclic ring, or _- be _{(CH 2 CH 2 O) q} ;
W is _{oxygen, -S (O) o -,} - N (R a) R l -, carbonyl, or Metanchiaru;
However, _{R i} is _{-CH 2 -C (T-NO s} ) (R e) (R f) or ^{_{- (N 2 O 2) -}} · M + or where _{R b, R c, R e} or When R _f is -T-NO _s or (C (R _e ) (R _f )) _k -T-NO _s , the subgroup represented by "-T-NO _s " in X is hydrogen, It may be an alkyl, alkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, heterocyclic ring or aryl group.
Compound of formula (II):

Where R _k is:

X is defined in this specification.
Compound of formula (III):

Where X is as defined herein;
R _i is R _i independently each case, wherein R _i is as defined herein;
Z is an aryl group; and A ₁ , A _2, and A ₃ contain other subunits of 5- or 6-membered monocyclic aromatic rings, and each A ₁ , A _2, and A ₃ is independently Is:
(1) C—R _o , where R _o is each independently hydrogen, alkyl, alkoxyalkyl, halogen or nitro group;
(2) N—R _p , where R _p is independently a covalent bond, hydrogen, alkyl, arylalkyl, aryl or heteroaryl group bonded to adjacent ring atoms in order to confer aromaticity to the ring. is there;
(3) sulfur atom;
(4) oxygen atom; or (5) B _a = B _b , wherein B _a and B _b are each independently a nitrogen atom or C—R _o , where R _o is as defined herein. Is.
Compound of formula (IV):

here,
R _m is an alkyl or aryl group; and X, Z, A ₁ , A ₂ and A ₃ are as defined herein.   Arylpropionic acid compounds in which the compound is nitrosated and / or nitrosylated, arylacetic acid compounds in which the nitrosated and / or nitrosylated compounds, nitrosated and / or nitrosylated enol-type anilides, or nitrosated and / or nitrosylated The compound according to claim 1, which is a modified oxicam compound.   Nitrosated and / or nitrosylated arylacetic acid or arylpropionic acid compounds are aceclofenac, alcofenac, amfenac, brofenac, diclofenac, etodac, felbinac, flurbiprofen, fenoprofen, fenbufen, ibuprofen, indomethacin , Indoprofen, ketoprofen, lonazolac, loxoprofen, mofezolac, miloprofen, naproxen, oxaprozin, pyrprofen, sulindac, thiaprofen or tolmethine; nitrosated and / or nitrosylated aryl acid compounds are aspirin, acemetacin, carprofenac, Diflunisal, etofenamate, full phenamic, full phenac, ketorolac, mek Phenomic, mefenamic or tolfenamic; nitrosated and / or nitrosylated enol-type anilide is tenidap; nitrosated and / or nitrosylated oxicam compound is droxicam, piroxicam, isoxicam, lornoxicam or ampiroxicam A compound according to claim 2.   A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.   Treating, preventing or reducing inflammation, pain and fever in a patient in need of treatment, prevention or alleviation, characterized in that a therapeutically effective amount of the pharmaceutical composition according to claim 4 is administered to the patient Method.   Treating or treating gastrointestinal, renal or other toxicities caused to a patient by the use of a non-steroidal anti-inflammatory compound, characterized by administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 4 How to recover.   A method for treating or preventing a gastrointestinal disorder in a patient in need of treatment or prevention, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition according to claim 4.   Gastrointestinal disorder is peptic ulcer, hyperacidity, dyspepsia, gastric paresis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, stress ulcer, hemorrhagic peptic ulcer, short bowel syndrome, or systemic mastocytosis or favorable 8. The method according to claim 7, wherein the hypersecretory state is associated with basic lymphocyte leukemia and hyperhistamineemia.   A method of treating an inflammatory disease or disorder in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 4.   Inflammatory disease or disorder is reperfusion injury to ischemic organ, myocardial infarction, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, hypertension, psoriasis, organ transplant rejection, organ preservation, female or male sexual function Failure, radiation-induced damage, asthma, atherosclerosis, thrombosis, platelet aggregation, restenosis, metastasis, influenza, incontinence, stroke, burn, trauma, acute pancreatitis, pyelonephritis, hepatitis, autoimmune disease, immunodeficiency, senile 10. The method according to claim 9, which is dementia, insulin-dependent diabetes mellitus, disseminated intravascular coagulation, fat embolism, Alzheimer's disease, adult or infant respiratory disease, carcinogenesis or bleeding in a newborn.   A method of treating or preventing an ophthalmic disease or disorder in a patient in need of treatment or prevention, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 4.   The method according to claim 11, wherein the ocular disease or disorder is glaucoma, ophthalmitis, or increased intraocular pressure.   At least one of the compounds according to claim 1 and donating, transferring or releasing nitric oxide, inducing the production of endogenous nitric oxide or endothelium-derived relaxing factor, or being a substrate for nitric oxide synthase A composition comprising at least one compound.   14. The compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is S-nitrosothiol. Composition.   S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine, or S-nitroso-glutathione 15. A composition according to claim 14, wherein: S-nitrosothiol is
(I) HS (C (R _e ) (R _f )) _m SNO;
(Ii) ONS (C (R _e ) (R _f )) _m R _e ; and (iii) H ₂ N—CH (CO ₂ H) — (CH ₂ ) _m —C (O) NH—CH (CH ₂ SNO) —C (O) NH—CH ₂ —CO ₂ H;
Where m is an integer from 2 to 20; R _e and R _f are each independently hydrogen, alkyl, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, aryl heterocyclic ring, alkylaryl, Cycloalkylalkyl, heterocyclic alkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, haloalkoxy, sulfonic acid, alkylsulfonic acid, arylsulfonic acid, aryl Alkoxy, alkylthio, arylthio, cyano, aminoalkyl, aminoaryl, alkoxy, aryl, arylalkyl, alkylaryl, carboxamide, alkylcarboxyl Amide, aryl carboxamide, amidyl, carboxyl, carbamoyl, alkyl carboxylic acid, aryl carboxylic acid, ester, carboxylic acid ester, alkyl carboxylic acid ester, aryl carboxylic acid ester, haloalkoxy, sulfonamide, alkyl sulfonamide, aryl sulfonamide, urea , Nitro, or —TQ; or R _e and R _f are bonded to each other to form a carbonyl group, a methanethiol, a heterocyclic ring, a cycloalkyl group, or a bridged cycloalkyl group; Is —NO or —NO ₂ ; and T is independently a covalent bond, carbonyl, oxygen, —S (O) _o — or —N (R _a ) R _i —, where o is from 0 an integer 2, R _a is a lone pair, hydrogen or an alkyl radical der ; R _i is hydrogen, alkyl, aryl, alkyl carboxylic acids, aryl carboxylic acids, alkyl carboxylic acid ester, arylcarboxylic acid ester, alkylcarboxamide, aryl carboxamide, alkylaryl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, sulfonamido amide, carboxamide, carboxylic acid esters, aminoalkyl, _{aminoaryl, -CH 2 -C (T-Q} ) (R e) (R f), or ^{_{- (N 2 O 2 -)}} - · M + is a, Where M ⁺ is an organic or inorganic cation; provided that R _i is —CH ₂ —C (TQ) (R _e ) (R _f ) or — (N ₂ O ₂ —) · M ⁺ "-TQ" is hydrogen, alkyl group, alkoxyalkyl group, aminoalkyl It may be a hydroxyl group or an aryl group, the composition according to claim 14.   Compounds that donate, transfer or release nitric oxide, induce the production of endogenous nitric oxide or endothelium-derived relaxing factor, or are substrates for nitric oxide synthase are L-arginine, L-homoarginine, N- 14. Hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine or glutamine The described composition. A compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase,
(I) a compound comprising at least one ON-O-, ON-N- or ON-C- group,
(Ii) a compound comprising at least one O ₂ N—O—, O ₂ N—N—, O ₂ N—S— or O ₂ N—C— group,
^{(Iii) R 1 R 2 -N} (O-M +) A N- oxo -N- nitrosamines represented by the formula -NO,
Where R ¹ and R ² are each independently a polypeptide, amino acid, sugar, oligonucleotide, linear or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or A heterocyclic group and M ⁺ is an organic or inorganic cation, or (iv) a thionitrate represented by the formula R ¹ — (S) —NO ₂ , wherein R ¹ is 14. A polypeptide, amino acid, sugar, oligonucleotide, linear or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or heterocyclic group. Composition.   A compound having at least one ON-O-, ON-N- or ON-C- group is an ON-O-polypeptide, an ON-N-polypeptide, an ON-C-polypeptide, an ON-O-amino acid, ON-N-amino acid, ON-C-amino acid, ON-O-sugar, ON-N-sugar, ON-C-sugar, ON-O-oligonucleotide, ON-N-oligonucleotide, ON-C-oligonucleotide Linear, branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON-O-hydrocarbon, linear or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic Or aromatic ON-N-hydrocarbon, linear or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON-C-hydrocarbon, ON-O-heterocyclic compound, ON N- heterocyclic compound, or a ON-C-heterocyclic compounds, compositions according to claim 18. A compound having at least one O ₂ N—O—, O ₂ N—N—, O ₂ N—S— or O ₂ N—C— group is an O ₂ N—O-polypeptide, O ₂ N—N - _{polypeptides,} O 2 N-S- _polypeptide, O 2 N-C- _polypeptide, O 2 N-O- amino _acid, O 2 N-N- amino _acid, O 2 N-S- amino _acid, O 2 N- C-amino acid, O ₂ N—O-sugar, O ₂ N—N-sugar, O ₂ N—S-sugar, O ₂ N—C-sugar, O ₂ N—O-oligonucleotide, O ₂ N—N - _{oligonucleotide,} O 2 N-S- _{oligonucleotides,} O 2 N-C-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted _O 2 N-O -Hydrocarbon, linear or branched, saturated or unsaturated, aliphatic or aromatic, substituted Others unsubstituted O _{2 N-N-} hydrocarbon, linear or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O _{2 N-S-} hydrocarbon, linear or Branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O ₂ N—C-hydrocarbon, O ₂ N—O-heterocyclic compound, O ₂ N—N-heterocyclic compound, The composition according to claim 18, which is an O ₂ N—S-heterocyclic compound or an O ₂ N—C-heterocyclic compound.   14. Treating, preventing or reducing inflammation, pain and fever in a patient in need of treatment, prevention or alleviation, characterized by administering to a patient a therapeutically effective amount of the pharmaceutical composition according to claim 13. Method.   14. Treating or ameliorating gastrointestinal, renal or other toxicities by a non-steroidal anti-inflammatory compound administered to a patient, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 13. how to.   A method for treating or preventing a gastrointestinal disorder in a patient in need of treatment or prevention, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 13.   Gastrointestinal disorder is peptic ulcer, hyperacidity, dyspepsia, gastric paresis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, stress ulcer, hemorrhagic peptic ulcer, short bowel syndrome, or systemic mastocytosis or favorable 24. The method according to claim 23, wherein the hypersecretory state is associated with basic lymphocyte leukemia and hyperhistamineemia.   14. A method of treating an inflammatory disease or disorder in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 13.   Inflammatory disease or disorder is reperfusion injury to ischemic organ, myocardial infarction, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, hypertension, psoriasis, organ transplant rejection, organ preservation, female or male sexual function Failure, radiation-induced damage, asthma, atherosclerosis, thrombosis, platelet aggregation, restenosis, metastasis, influenza, incontinence, stroke, burn, trauma, acute pancreatitis, pyelonephritis, hepatitis, autoimmune disease, immunodeficiency, senile 26. The method according to claim 25, which is dementia, insulin-dependent diabetes mellitus, disseminated intravascular coagulation, fat embolism, Alzheimer's disease, adult or infant respiratory disease, carcinogenesis or bleeding in a newborn.   A method for treating or preventing an ophthalmic disease or disorder in a patient in need of treatment or prevention, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 13.   28. The method of claim 27, wherein the ophthalmic disease or disorder is glaucoma, ophthalmitis or increased intraocular pressure.   A kit comprising at least one compound according to claim 1.   At least one of the compounds according to claim 1 and donating, transferring or releasing nitric oxide, inducing the production of endogenous nitric oxide or endothelium-derived relaxing factor, or being a substrate for nitric oxide synthase A kit comprising at least one compound.   32. The compound of claim 30, wherein the compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is S-nitrosothiol. Kit.   S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine, or S-nitroso-glutathione 32. The kit according to claim 31, wherein: S-nitrosothiol is
(I) HS (C (R _e ) (R _f )) _m SNO;
(Ii) ONS (C (R _e ) (R _f )) _m R _e ; and (iii) H ₂ N—CH (CO ₂ H) — (CH ₂ ) _m —C (O) NH—CH (CH ₂ SNO) —C (O) NH—CH ₂ —CO ₂ H;
Where m is an integer from 2 to 20; R _e and R _f are each independently hydrogen, alkyl, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, aryl heterocyclic ring, alkylaryl, Cycloalkylalkyl, heterocyclic alkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, haloalkoxy, sulfonic acid, alkylsulfonic acid, arylsulfonic acid, aryl Alkoxy, alkylthio, arylthio, cyano, aminoalkyl, aminoaryl, alkoxy, aryl, arylalkyl, alkylaryl, carboxamide, alkylcarboxyl Amide, aryl carboxamide, amidyl, carboxyl, carbamoyl, alkyl carboxylic acid, aryl carboxylic acid, ester, carboxylic acid ester, alkyl carboxylic acid ester, aryl carboxylic acid ester, haloalkoxy, sulfonamide, alkyl sulfonamide, aryl sulfonamide, urea , Nitro, or —TQ; or R _e and R _f are bonded to each other to form a carbonyl group, a methanethiol, a heterocyclic ring, a cycloalkyl group, or a bridged cycloalkyl group; Is —NO or —NO ₂ ; and T is independently a covalent bond, carbonyl, oxygen, —S (O) _o — or —N (R _a ) R _i —, where o is from 0 an integer 2, R _a is a lone pair, hydrogen or an alkyl radical der ; R _i is hydrogen, alkyl, aryl, alkyl carboxylic acids, aryl carboxylic acids, alkyl carboxylic acid ester, arylcarboxylic acid ester, alkylcarboxamide, aryl carboxamide, alkylaryl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, sulfonamido amide, carboxamide, carboxylic acid esters, aminoalkyl, _{aminoaryl, -CH 2 -C (T-Q} ) (R e) (R f), or ^{_{- (N 2 O 2 -)}} - · M + is a, Where M ⁺ is an organic or inorganic cation; provided that R _i is —CH ₂ —C (TQ) (R _e ) (R _f ) or — (N ₂ O ₂ —) · M ⁺ "-TQ" is hydrogen, alkyl group, alkoxyalkyl group, aminoalkyl It may be a hydroxyl group or an aryl group, a kit according to claim 31.   Compounds that donate, transfer or release nitric oxide, induce the production of endogenous nitric oxide or endothelium-derived relaxing factor, or are substrates for nitric oxide synthase are L-arginine, L-homoarginine, N- 31. Hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine or glutamine The kit described. A compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase,
(I) a compound comprising at least one ON-O-, ON-N- or ON-C- group,
(Ii) a compound comprising at least one O ₂ N—O—, O ₂ N—N—, O ₂ N—S— or O ₂ N—C— group,
^{(Iii) R 1 R 2 -N} (O-M +) A N- oxo -N- nitrosamines represented by the formula -NO,
Where R ¹ and R ² are each independently a polypeptide, amino acid, sugar, oligonucleotide, linear or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or A heterocyclic group and M ⁺ is an organic or inorganic cation, or (iv) a thionitrate represented by the formula R ¹ — (S) —NO ₂ , wherein R ¹ is 31. A polypeptide, amino acid, sugar, oligonucleotide, linear or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or heterocyclic group. Kit.   A compound having at least one ON-O-, ON-N- or ON-C- group is an ON-O-polypeptide, an ON-N-polypeptide, an ON-C-polypeptide, an ON-O-amino acid, ON-N-amino acid, ON-C-amino acid, ON-O-sugar, ON-N-sugar, ON-C-sugar, ON-O-oligonucleotide, ON-N-oligonucleotide, ON-C-oligonucleotide Linear, branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON-O-hydrocarbon, linear or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic Or aromatic ON-N-hydrocarbon, linear or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON-C-hydrocarbon, ON-O-heterocyclic compound, ON N- heterocyclic compound, or a ON-C-heterocyclic compounds, kits according to claim 35. A compound having at least one O ₂ N—O—, O ₂ N—N—, O ₂ N—S— or O ₂ N—C— group is an O ₂ N—O-polypeptide, O ₂ N—N - _{polypeptides,} O 2 N-S- _polypeptide, O 2 N-C- _polypeptide, O 2 N-O- amino _acid, O 2 N-N- amino _acid, O 2 N-S- amino _acid, O 2 N- C-amino acid, O ₂ N—O-sugar, O ₂ N—N-sugar, O ₂ N—S-sugar, O ₂ N—C-sugar, O ₂ N—O-oligonucleotide, O ₂ N—N - _{oligonucleotide,} O 2 N-S- _{oligonucleotides,} O 2 N-C-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted _O 2 N-O -Hydrocarbon, linear or branched, saturated or unsaturated, aliphatic or aromatic, substituted Others unsubstituted O _{2 N-N-} hydrocarbon, linear or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O _{2 N-S-} hydrocarbon, linear or Branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O ₂ N—C-hydrocarbon, O ₂ N—O-heterocyclic compound, O ₂ N—N-heterocyclic compound, O ₂ N-S- heterocyclic compound, or _O 2 N-C-heterocyclic compounds, kits according to claim 35.   2- [4-Methyl-4- (nitrosothio) piperidyl] ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate hydrochloride; 2- (methyl {[(nitrosothio) cyclohexyl] methyl} amino ) Ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate hydrochloride; 2- (methyl {[(nitrosothio) cyclohexyl] methyl} amino) ethyl (2S) -2- (6-methoxy ( 2-naphthyl)) propanoate hydrochloride; 3- (methyl {[(nitrosothio) cyclohexyl] methyl} amino) propyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate; 4-({ Methyl [2-methyl-2- (nitrosothio) propyl] amino} methyl) phenyl (2S) -2- (6-methoxy (2-naphthy) )) Propanoate hydrochloride; 2- {4- (nitrosothio) -4-piperidyl] ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate hydrochloride; 2- [2- (2 -{2-[(2,6-dichlorophenyl) amino] phenyl} acetoxy) ethoxy] ethyl 3- (N-{[(nitrosothio) cyclohexyl] methyl} -N-benzylcarbamoyl) propanoate; 2- {4- [2 -Methyl-2- (nitrosothio) propyl] piperazinyl} ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate citrate; 2- [2-tert-butyl) -5- (nitrosothio)- 1,3-dioxane-5-yl] ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate; 5- (bis {[(nitrosothio) Chlohexyl] methyl} amino) pentyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate; 2-({3-[(2S) -2- (6-methyl (2-naphthyl)) propanoyl Oxy] propyl} {[(nitrosothio) cyclohexyl] methyl} amino) acetic acid; 3- (methyl {[1-methyl-4- (nitrosothio) (4-piperidyl)] methyl} amino) propyl 2- {2-[( 2,6-dichlorophenyl) amino] phenyl} acetate; 2- [1-methyl-4- (nitrosothio) -4-piperidyl] ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate citrate 2- [1-methyl-4- (nitrosothio) -4-piperidyl] ethyl 2- [4- (2-methylpropyl) phenyl] propanoate citrate; 2- [1-methyl-4- (nitro Thio) -4-piperidyl] ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate citrate; 2- [1-methyl-4- (nitrosothio) -4-piperidyl] ethyl 2- [3- (phenylcarbonyl) phenyl] propanoate citrate; 2- [1-methyl-4- (nitrosothio) -4piperidyl] ethyl 2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy- 2-methylindol-3-yl} acetate citrate; 2- (methyl [2-methyl {[(nitrosothiol) cyclohexyl] methyl} amino) ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl } Acetate bis-nitrate; 2- (methyl [2-methyl {[(nitrosothiol) cyclohexyl] methyl} amino) ethyl 2- {1-[(4-chlorophenyl) carbo Nyl] -5-methoxy-2-methylindol-3-yl} acetate; 2-{[(dimethylamino) ethyl] {[(nitrosothio) cyclohexyl] methyl} amino) ethyl 2- {2-[(2,6 -Dichlorophenyl) amino] phenyl} acetate; 2- [4-methyl-4- (nitrosothio) piperidyl] ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate; 2- (methyl {[1- Methyl-4- (nitrosothio) (4-piperidyl)] methyl} amino) ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate hydrochloride; 3- [4-methyl-4- ( Nitrosothio) piperidyl] propyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate; 3- [4-methyl-4- (nitrosothio) piperidyl] propyl (2 S) -2- (6-methoxy (2-naphthyl)) propanoate; 2- [2-({N- [2-methyl-2- (nitrosothio) propyl] carbamoyl} methoxy) acetylamino] ethyl 2- {2 -[(2,6-dichlorophenyl) amino] phenyl} acetate; [2-({N- [2-methyl-2- (nitrosothio) propyl] carbamoyl} methoxy) acetyloxy] methyl 2- {2-[(2 , 6-dichlorophenyl) amino] phenyl} acetate; 2- [4- (nitrosothio) -4-piperidyl] ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate hydrochloride; {[3 -(Methyl {[(nitrosothio) cyclohexyl] methyl} amino) propyl] oxycarbonyl} methyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate; 2- {4 [3-Methyl-3- (nitrosothio) butanoyl] piperazinyl} ethyl 2- {2-[(2,6-dichlorophenyl) methyl] phenyl} acetate; {4- [dicyclopropyl (nitrosothio) methyl] -1-methyl -4-piperidyl} methyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate; 2- {2-[(2,6-dichlorophenyl) amino] phenyl} -1- (2- {methyl [ 2-methyl-2- (nitrosothio) propyl] amino} ethylthio) ethane-1-one hydrochloride; 2- {2-[(2,6-dichlorophenyl) amino] phenyl} -1- [2- (methyl {[ (Nitrosothio) cyclohexyl] methyl} amino) ethylthio] ethane-1-one; 4-({ethyl [2-methyl-2- (nitrosothio) propyl] amino} methyl) phenyl 2- {2-[(2, -Dichlorophenyl) amino] phenyl} acetate; (2R, 3R) -2,3-dihydroxy-3- {N- [2-methyl-2- (nitrosothio) propyl] carbamoyl} propyl 2- {2-[(2, 6-dichlorophenyl) amino] phenyl} acetate; 2- {1- [2-methyl-2- (nitrosothio) propyl] -4-piperidyl} ethyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} Acetate; {(2S) -1- [2-Methyl-2- (nitrosothio) propyl] pyrrolidin-2-yl} methyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate; 2-({ 4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} ethoxy) ethyl 2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindo -3-yl} acetate; 2- (2- {4- [2-methyl-2- (nitrosothio) propyl] piperazinyl} ethoxy) ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate; 4-({4- [2-Methyl-2- (nitrosothio) propyl] piperazinyl} methyl) phenyl 2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} Acetate; 5-({4- [2-methyl-2- (nitrosothio) propyl] piperazinyl} carbonyl) -2pyridyl 2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindole- 3-yl} acetate; 5-({4- [2-methyl-2- (nitrosothio) propyl] piperazinyl} carbonyl) -2pyridyl 2- {1-[(4-chlorophenyl) carbonyl]- 5-methoxy-2-methylindol-3-yl} acetate; 2-([2- (2- {1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} acetyl Oxy] ethyl) {[(nitrosothio) cyclohexyl] methyl] amino} acetic acid; 2- (methyl {1- [2-methyl-2- (nitrosothio) propyl] (4-piperidyl)} amino) ethyl (2S) -2 -(6-Methoxy (2-naphthyl)) propanoate; 3-{(4S) -4- [1-methyl-1- (nitrosothio) ethyl] -2-oxo-1,3-oxazolidin-3-yl} propyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate; {ethoxy [3-methyl-3- (nitrosothio) butoxy] phosphonyl} methyl (2S) -2- (6-methoxy (2-naphthyl) Propano 6- (4-{[2-methyl-2- (nitrosothio) propyl] amino} pyrimidin-2-ylthio) hexyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate; {(2S , 5S) -5- [1-methyl-1- (nitrosothio) ethyl] -3,6-dioxopiperazin-2-yl} methyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate; 2- (N-methyl {1- [2-methyl-2- (nitrosothio) propyl] (4-piperidyl)} carbonylamino) ethyl (2S) -2- (6-methoxy (2-naphthyl)) propanoate; 4 -({4- [2-methyl-2- (nitrosothio) propyl] piperazinyl} carbonyl) phenyl 2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetate; and 3-[(2S) -2 − A compound selected from the group consisting of (6-methoxy (2-naphthyl) propanoyloxy] -2-oxopropyl-3-methyl-3- (nitrosothio) butanoate.   40. A composition comprising at least one compound as claimed in claim 38 and a pharmaceutically acceptable carrier.